U.S. patent number 10,330,763 [Application Number 16/044,393] was granted by the patent office on 2019-06-25 for selective sampling for assessing structural spatial frequencies with specific contrast mechanisms.
This patent grant is currently assigned to BIOPROTONICS INC.. The grantee listed for this patent is bioProtonics, LLC. Invention is credited to Kristin James, Timothy W. James.
![](/patent/grant/10330763/US10330763-20190625-D00000.png)
![](/patent/grant/10330763/US10330763-20190625-D00001.png)
![](/patent/grant/10330763/US10330763-20190625-D00002.png)
![](/patent/grant/10330763/US10330763-20190625-D00003.png)
![](/patent/grant/10330763/US10330763-20190625-D00004.png)
![](/patent/grant/10330763/US10330763-20190625-D00005.png)
![](/patent/grant/10330763/US10330763-20190625-D00006.png)
![](/patent/grant/10330763/US10330763-20190625-D00007.png)
![](/patent/grant/10330763/US10330763-20190625-D00008.png)
![](/patent/grant/10330763/US10330763-20190625-D00009.png)
![](/patent/grant/10330763/US10330763-20190625-D00010.png)
View All Diagrams
United States Patent |
10,330,763 |
James , et al. |
June 25, 2019 |
Selective sampling for assessing structural spatial frequencies
with specific contrast mechanisms
Abstract
The disclosed embodiments provide a method for acquiring MR data
at resolutions down to tens of microns for application in in vivo
diagnosis and monitoring of pathology for which changes in fine
tissue textures can be used as markers of disease onset and
progression. Bone diseases, tumors, neurologic diseases, and
diseases involving fibrotic growth and/or destruction are all
target pathologies. Further the technique can be used in any
biologic or physical system for which very high-resolution
characterization of fine scale morphology is needed. The method
provides rapid acquisition of signal at selected values in k-space,
with multiple successive acquisitions at individual k-values taken
on a time scale on the order of microseconds, within a defined
tissue volume, and subsequent combination of the multiple
measurements in such a way as to maximize SNR. The reduced
acquisition volume, and acquisition of only signal values at select
places in k-space, along selected directions, enables much higher
in vivo resolution than is obtainable with current MRI
techniques.
Inventors: |
James; Kristin (Santa Barbara,
CA), James; Timothy W. (Santa Barbara, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
bioProtonics, LLC |
Santa Ynez |
CA |
US |
|
|
Assignee: |
BIOPROTONICS INC. (Santa Ynez,
CA)
|
Family
ID: |
59786379 |
Appl.
No.: |
16/044,393 |
Filed: |
July 24, 2018 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20180329009 A1 |
Nov 15, 2018 |
|
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
15604465 |
May 24, 2017 |
10061003 |
|
|
|
15288974 |
May 30, 2017 |
9664760 |
|
|
|
15167828 |
May 30, 2017 |
9664759 |
|
|
|
14840327 |
Jun 14, 2016 |
9366738 |
|
|
|
62044321 |
Sep 1, 2014 |
|
|
|
|
62064206 |
Oct 15, 2014 |
|
|
|
|
62107465 |
Jan 25, 2015 |
|
|
|
|
62302577 |
Mar 2, 2016 |
|
|
|
|
62238121 |
Oct 7, 2015 |
|
|
|
|
62382695 |
Sep 1, 2016 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01R
33/4818 (20130101); G01R 33/5602 (20130101); G01R
33/5619 (20130101); G01R 33/5601 (20130101); G06T
7/0012 (20130101); G01R 33/4833 (20130101); A61B
5/055 (20130101); G01R 33/4835 (20130101); A61B
5/7203 (20130101); G01R 33/56341 (20130101); G06T
2207/10088 (20130101); G01R 33/5617 (20130101); G01R
33/50 (20130101); A61B 5/7207 (20130101); A61B
2560/0238 (20130101); G01R 33/5616 (20130101) |
Current International
Class: |
G01R
33/56 (20060101); A61B 5/00 (20060101); G01R
33/561 (20060101); G01R 33/483 (20060101); G01R
33/48 (20060101); G01R 33/563 (20060101); G06T
7/00 (20170101); A61B 5/055 (20060101); G01R
33/50 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Vargas; Dixomara
Attorney, Agent or Firm: Fischer; Felix L.
Parent Case Text
REFERENCE TO RELATED APPLICATIONS
This application is a divisional of application Ser. No. 15/604,465
filed on May 24, 2017 which is a continuation in part of
application Ser. No. 15/288,974 filed on Oct. 7, 2016, now U.S.
Pat. No. 9,664,760, which is a continuation in part of Ser. No.
15/167,828 filed on May 27, 2016, now U.S. Pat. No. 9,664,759,
which is a continuation in part of application Ser. No. 14/840,327
filed on Aug. 31, 2015, now U.S. Pat. No. 9,366,738. Application
Ser. No. 14/840,327 relies on the priority of U.S. provisional
application Ser. No. 62/044,321 filed on Sep. 1, 2014 entitled
SELECTIVE SAMPLING MAGNETIC RESONANCE-BASED METHOD FOR ASSESSING
STRUCTURAL SPATIAL FREQUENCIES, Ser. No. 62/064,206 filed on Oct.
15, 2014 having the same title and Ser. No. 62/107,465 filed on
Jan. 25, 2015 entitled MICRO-TEXTURE CHARACTERIZATION BY MRI, the
disclosures of which are incorporate herein by reference.
Application Ser. No. 15/167,828 additionally relies on the priority
of provisional application Ser. No. 62/302,577 filed on Mar. 2,
2016 entitled METHOD FOR ASSESSING STRUCTURAL SPATIAL FREQUENCIES
USING HYBRID SAMPLING WITH LOW OR INCREASED GRADIENT FOR
ENHANCEMENT OF VERY LOW NOISE SELECTIVE SAMPLING WITH NO GRADIENT.
Application Ser. No. 15/288,974 relies on the priority of U.S.
provisional application Ser. No. 62/238,121 filed on Oct. 7, 2015
entitled SELECTIVE SAMPLING MAGNETIC RESONANCE-BASED METHOD FOR
ASSESSING STRUCTURAL SPATIAL FREQUENCIES and provisional
application Ser. No. 62/382,695 filed on Sep. 1, 2016 entitled
SELECTIVE SAMPLING FOR ASSESSING STRUCTURAL SPATIAL FREQUENCIES
WITH SPECIFIC CONTRAST MECHANISMS. The referenced applications all
have a common assignee with the present application and the
disclosures thereof are incorporated herein by reference.
Claims
What is claimed is:
1. A method for calibration of Magnetic Resonance (MR) tissue
texture measurement comprising: using microCT, MRI microscopy, or
pathology to obtain high resolution 2D or 3D tissue data sets from
selected tissue samples; simulating data acquisition using the data
sets as input for applying a selected contrast mechanism,
selectively exciting a simulated volume of interest (VOI) employing
a plurality of simulated time varying radio frequency signals and
applied gradients, applying a simulated encoding gradient pulse to
induce phase wrap to create a spatial encode for a specific k-value
and orientation, the specific k-value determined based on the
texture within the VOI, initiating a series of simulated gradients
to produce k-value encodes, a resulting k-value set being a subset
of that required to produce an image of the VOI, recording multiple
sequential samples of simulated NMR RF signal encoded with the
k-value set and post processing the recorded NMR signal samples to
produce a data set of signal vs k-values for k-values in the
k-value set, to characterize a simulation of the textural features
of tissue in the VOI; comparing features in the 2D/3D data sets
with the simulation of textural features to provide comparative
datasets; repeating the step of simulating data acquisition across
a high number of VOIs positioned within the tissue datasets;
applying supervised machine learning to the simulation of textual
features and to the comparative datasets to optimize acquisition
parameters including VOI dimensions and acquisition direction,
using best resolution of the targeted feature measure as an
endpoint.
2. The method as defined in claim 1 further comprising: using
unsupervised machine learning across the defined VOIs in tissue
with specific disease markers to identify salient features
additional to that called out for supervised learning; using
machine learning algorithms to correlate those features with
information known regarding disease onset and progression in the
tissue samples towards biomarker identification; determining a
sparsely sampled data set needed for measuring the tissue
biomarkers towards a disease diagnostic assessment; using machine
learning algorithms to determine the strength of the diagnostic
assessment; acquiring data in the actual SNR environment of a MR
scanner by applying the selected contrast mechanism, selectively
exciting a volume of interest (VOI) employing a plurality of time
varying radio frequency signals and applied gradients, applying an
encoding gradient pulse to induce phase wrap to create a spatial
encode for a specific k-value and orientation, the specific k-value
determined based on texture within the VOI, initiating a series of
gradients to produce k-value encodes, a resulting k-value set being
a subset of that required to produce an image of the VOI, recording
multiple sequential samples of the NMR RF signal encoded with the
k-value set and post processing the recorded NMR signal samples to
produce a data set of signal vs k-values for k-values in the
k-value set, to characterize textural features of tissue in the
VOI, on the same tissue samples, for comparison to the ground truth
datasets; repeating the recited steps to obtain optimization of
acquisition parameters and calibration of the embodiments disclosed
towards high resolution, robust textural measure.
3. A method for interpretation of Magnetic Resonance (MR) tissue
texture measurement for determining pathology of a tissue type
comprising: selecting a contrast mechanism enhancing the contrast
between component tissue types in a multiphase biologic sample for
measurement with a MR imaging process; applying the selected
contrast mechanism; selectively exciting a volume of interest (VOI)
employing a plurality of time varying radio frequency signals and
applied gradients; applying an encoding gradient pulse to induce
phase wrap to create a spatial encode for a specific k-value and
orientation, the specific k-value determined based on texture
within the VOI; initiating a series of gradients to produce k-value
encodes, a resulting k-value set being a subset of that required to
produce an image of the VOI; recording multiple sequential samples
of the NMR RF signal encoded with the k-value set; post processing
the recorded NMR signal samples to produce a data set of signal vs
k-values for k-values in the k-value set, to characterize textural
features of tissue in the VOI; and applying machine learning to a
power density distribution of a textural wavelength of the k-value
set to identify bio-markers for diagnosis of pathology of the
tissue.
4. The method of claim 3 further comprising applying machine
learning to identify a correlation between textural features and
features in a power density spectrum of the textural
wavelengths.
5. The method of claim 3 further comprising applying machine
learning to the textural features and diagnostic information
sources using additional sources of diagnostic information such as
patient histories, exam records, imaging, serum markers, physical
performance, and cognitive tests for extraction of diagnostic data
to determine a disease assessment.
6. The method of claim 5 further comprising applying machine
learning to determine weighting of the various diagnostic
information sources in the ultimate diagnosis.
7. The method of claim 3 further comprising: selecting a plurality
of biologic phantoms having tissue pathology from healthy through
diseased; selecting a contrast mechanism enhancing the contrast
between component tissue types in each biologic phantom for
measurement with a MR imaging process; applying the selected
contrast mechanism; selectively exciting a volume of interest (VOI)
in each biologic phantom employing a plurality of time varying
radio frequency signals and applied gradients; applying an encoding
gradient pulse to induce phase wrap to create a spatial encode for
a specific k-value and orientation, the specific k-value determined
based on texture within the VOI; initiating a series of gradients
to produce k-value encodes, a resulting k-value set being a subset
of that required to produce an image of the VOI; and, recording
multiple sequential samples of the NMR RF signal encoded with the
k-value set to provide texture measurement of each of the biologic
phantoms. post processing the recorded NMR signal samples to
produce a data set of signal vs k-values for k-values in the
k-value set, to characterize textural features of tissue in the
VOI.
8. A method for pathology assessment employing tissue texture using
magnetic resonance (MR) comprising: selectively exciting a volume
of interest (VOI) in tissue subject to motion employing a plurality
of time varying radio frequency signals and applied gradients;
applying an encoding gradient pulse to induce phase wrap to create
a spatial encode for a specific k-value and orientation, the
specific k-value determined based on texture within the VOI;
initiating a series of gradients to produce k-value encodes giving
a resulting k-value set; recording multiple sequential samples of
the NMR RF signal encoded with the k-value set within a single
excitation of the VOI, the selectively excited VOI moving with the
tissue; post processing the recorded NMR signal samples to produce
a data set of signal vs k-values for k-values in the k-value set,
to characterize textural features of tissue in the VOI.
Description
BACKGROUND
Field of the Invention
The herein claimed method relates to the field of diagnostic
assessment of fine textures in biological systems for pathology
assessment and disease diagnosis, and in material and structural
evaluation in industry and in engineering research. More
specifically, the embodiments disclosed herein provide methods for
repeat measurement of signal at k-values associated with the
spatial organization of biologic tissue texture, with the MRI
machine gradients turned off and at k-values in an associated
neighborhood with a low gradient applied during signal acquisition.
Various contrast mechanisms can be used in conjunction with the
embodiments disclosed herein; in cases of novel contrast
mechanisms, such as DWI, DTI, or ASL, which, in addition to
changing timing, may require additional tailored RF and gradient
pulses, the novel contrast can be incorporated into the embodiment,
forming an integrated sequence; another method would be one wherein
data acquisition by the novel contrast sequence is run in parallel
with data acquisition by the disclosed embodiments and the data
compared, with the data obtained by the embodiments disclosed
providing direct measure of the fine tissue texture for calibrating
and understanding the data obtained by another contrast method.
That is, the use of varying contrast methods allows use of the
embodiments in conjunction with other MRI imaging and measurement
methods either in an integrated form, wherein the timing and any
additional RF and gradient pulses used to set contrast are combined
into one pulse sequence, or in parallel operation wherein data
acquired using the disclosed embodiments is acquired and compared
as a calibration/complimentary assessment of the data acquired by
other contrast mechanisms. The data obtained either by the
integrated method or the complementary method can further be mapped
across a region of tissue to assess the spatial variation in
pathology. The methods enable in vivo assessment, towards diagnosis
and monitoring of disease and therapy-induced textural changes in
tissue. Representative targets of the technique are: 1) for
assessment of changes to trabecular architecture caused by bone
disease, allowing assessment of bone health and fracture risk; 2)
evaluation of fibrotic development in soft tissue diseases such as,
for example, liver, lung, and heart disease; 3) changes to fine
structures in neurologic diseases, such as, for example, the
various forms of dementia, Multiple Sclerosis (MS), or in cases of
brain injury and downstream neuropathology as in, for example,
Traumatic Brain Injury (TBI) and Chronic Traumatic Encephalopathy
(CTE), or for characterization and monitoring of abnormal
neurologic conditions such as autism and schizophrenia; 4)
assessment of vascular changes such as in the vessel network
surrounding tumors or associated with development of CVD
(Cerebrovascular Disease), and of changes in mammary ducting in
response to tumor growth; 5) assessment of fibrotic diseases, from
lung and liver fibrosis, to cardiac and cystic fibrosis, pancreatic
fibrosis, muscular dystrophy, bladder and heart diseases, and
myelofibrosis, in which fibrotic structures replace bone marrow,
cancers, such as breast cancer and prostate cancer, muscle
diseases, such as Central Core Disease, in which the lobular
formations in muscle become infiltrated with fibrotic development;
6) lung disease diagnosis such as Idiopathic Pulmonary Fibrosis
(IPF). The invention also has applications in assessment of fine
structures for a range of industrial purposes such as measurement
of material properties in manufacturing or in geology to
characterize various types of rock, as well as other uses for which
measurement of fine structures/textures is needed.
Description of the Related Art
Though fine textural changes in tissue have long been recognized as
the earliest markers in a wide range of diseases, robust clinical
assessment of fine texture remains elusive, the main difficulty
arising from blurring caused by subject motion over the time
required for data acquisition.
Early and accurate diagnosis is key to successful disease
management. Though clinical imaging provides much information on
pathology, many of the tissue changes that occur as a result of
disease onset and progression, or as a result of therapy, are on an
extremely fine scale, often down to tens of microns. Changes in
fine tissue texture have been recognized for many years by
diagnosticians, including radiologists and pathologists as the
earliest harbinger of a large range of diseases, but in vivo
assessment and measurement of fine texture has remained outside the
capabilities of current imaging technologies. For instance,
differential diagnosis of obstructive lung disease relies on a
textural presentation in the lung parenchyma, but the robustness of
the Computed Tomography (CT) measure of early stage disease is
limited. Trabecular bone microarchitecture, the determinant of
fracture risk in aging bone, has also remained elusive due to image
blurring from patient motion during Magnetic Resonance (MR) imaging
scans. Post processing analysis of MR-images is sometimes used to
try to differentiate image textures in structures such as tumors
and white matter. (DRABYCZ, S., et al.; "Image texture
characterization using the discrete orthogonal S-transform";
Journal of Digital Imaging, Vol. 22, No 6, 2009. KHIDER, M., et
al.; "Classification of trabecular bone texture from MRI and CT
scan images by multi-resolution analysis"; 29th Annual
International Conference of the IEEE Engineering in Medicine and
Biology Society, EMBS 2007.) But post processing analysis is
limited in effect as it doesn't deal with the underlying problem
that prevents high resolution acquisition of textural information,
i.e. subject motion. (MACLAREN, J. et al.; "Measurement and
correction of microscopic head motion during magnetic resonance
imaging of the brain", PLOS/ONE, Nov. 7, 2012. MACLARAN, J. et al.;
"Prospective motion correction in brain imaging: a review; Magnetic
Resonance in Medicine, Vol. 69, 2013.)
The main sources of motion affecting MR imaging are cardiac
pulsatile motion, respiratory-induced motion and twitching. The
first two are quasi-cyclic, the usual approach to which is gating
at the slowest phase of motion. However, even with gating, there is
sufficient motion between acquisitions to cause loss of spatial
phase coherence at the high k-values of interest for texture
measurements. This problem is exacerbated by the fact that motion
may not be perfectly cyclic, and often originates from combined
sources. Twitching is rapid, inducing random displacements, and
hence it is not possible to maintain coherence at the high k-values
of interest when measuring texture.
While Positron Emission Tomography (PET) provides valuable
diagnostic information, it is not capable of resolution below about
5 mm and relies on the use of radioactive tracers for imaging as
well as x-ray beams for positioning, raising dose concerns,
especially if repeat scanning is needed. (BERRINGTON DE GONZALEZ,
A. et al.; "Projected cancer risks from Computed Tomographic scans
performed in the United States in 2007"; JAMA Internal Medicine,
Vol. 169, No. 22, December 2009.) Further, PET imaging is extremely
costly, requiring a nearby cyclotron. CT resolution down to 0.7 mm
is possible in theory, though this is obtained at high radiation
dose and is subject to reduction by patient motion over the few
minute scan time. The non-negligible risk from the associated
radiation dose makes CT problematic for longitudinal imaging and
limits available resolution. Along with serious dose concerns,
digital x-ray resolution is limited because the 2-dimensional image
obtained is a composite of the absorption through the entire
thickness of tissue presented to the beam. Current clinical
diagnostics for the diseases that are the target of the embodiments
disclosed herein are fraught with difficulties in obtaining
sufficient in vivo resolution, or accuracy. In some cases, no
definitive diagnostic exists currently. In other pathologies,
particularly in breast and liver, diagnosis is dependent on biopsy,
with its non-negligible risk of morbidity and even mortality, and
which is prone to high read and sampling errors. (WELLER, C;
"Cancer detection with MRI as effective as PET-CT scan but with
zero radiation risks"; Medical Daily, Feb. 18, 2014.)
Bone health is compromised by ageing, by bone cancer, as a side
effect of cancer treatments, diabetes, rheumatoid arthritis, and as
a result of inadequate nutrition, among other causes. Bone disease
affects over ten million people annually in the US alone, adversely
affecting their quality of life and reducing life expectancy. For
assessment of bone health, the current diagnostic standard is Bone
Mineral Density (BMD), as measured by the Dual Energy X-ray
Absorptiometry (DEXA) projection technique. This modality yields an
areal bone density integrating the attenuation from both cortical
and trabecular bone, similar to the imaging mechanism of standard
x-ray, but provides only limited information on trabecular
architecture within the bone, which is the marker linked most
closely to bone strength. (KANIS, J. AND GLUER, C.; "An update on
the diagnosis and assessment of osteoporosis with densitometry";
Osteoporosis International, Vol. 11, issue 3, 2000. LEGRAND, E. et
al.; "Trabecular bone microarchitecture, bone mineral density, and
vertebral fractures in male osteoporosis"; JBMR, Vol. 15, issue 1,
2000.) BMD correlates only loosely with fracture risk. A
post-processing technique, TBS (Trabecular Bone Score) attempts to
correlate the pixel gray-level variations in the DEXA image, to
yield information on bone microarchitecture. A comparison study
determined that BMD at hip remains a better predictor of fracture.
But, though TBS does not yield a detailed assessment of trabecular
architecture. (BOUSSON, V., et al.; "Trabecular Bone Score (TBS):
available knowledge, clinical relevance, and future prospects";
Osteoporosis International, Vol. 23, 2012. DEL RIO, et al.; "Is
bone microarchitecture status of the spine assessed by TBS related
to femoral neck fracture? A Spanish case-control study":
Osteoporosis International, Vol. 24, 2013.) TBS is a relatively new
technique and is still being evaluated.
Measurement of bone microarchitecture, specifically trabecular
spacing and trabecular element thickness, requires resolution on
the order of tenths of a millimeter. MRI, ultrasound imaging, CT,
and microCT have all been applied to this problem. In MRI, though
high contrast between bone and marrow is readily obtained,
resolution is limited by patient motion over the long time needed
to acquire an image with sufficient resolution to characterize the
trabecular network. The finer the texture size of this network, the
greater the blurring from motion. An attempt to mitigate the
effects of patient motion by looking only at the skeletal
extremities, removed from the source of cardiac and respiratory
motion sources, has been tried using both MRI and microCT. However,
the correlation between bone microarchitecture in the extremities
and that in central sites in not known. Further, a large data
matrix, hence long acquisition time, is still required to obtain
sufficient image information to determine trabecular spacing and
element thickness. This long acquisition time results in varying
levels of motion-induced blurring, depending on patient
compliance--twitching is still a serious problem even when
measuring extremities. A proposed MR-based technique, fineSA
(JAMES, T., CHASE, D.; "Magnetic field gradient structure
characteristic assessment using one dimensional (1D)
spatial-frequency distribution analysis"; U.S. Pat. No. 7,932,7207;
Apr. 26, 2011.), attempts to circumvent the problem of patient
motion by acquiring a much smaller data matrix of successive,
finely-sampled, one-dimensional, frequency-encoded acquisitions
which are subsequently combined to reduce noise. Imaging in this
case is reduced to one dimension, reducing the size of the data
matrix acquired and, hence, the acquisition time. However, as the
gradient encoded echoes, are very low Signal to Noise (SNR), noise
averaging is required. Though some resolution advantage is gained
by this method relative to 2 and 3-d imaging, the need to acquire
many repeat spatially-encoded echoes over several response times
(TRs) for signal averaging results in an acquisition time on the
order of minutes--too long to provide motion immunity. Thus,
resolution improvement obtainable by the technique is limited.
What is needed is an accurate, robust, non-invasive, in vivo
measure of trabecular spacing and trabecular element thickness
capable of assessing bones in the central skeleton, as these are
the key markers for assessing bone health and predicting fracture
risk. Until now, no clinical technique has been able to provide
this capability.
Fibrotic diseases occur in response to a wide range of biological
insults and injury in internal organs, the development of collagen
fibers being the body's healing response. The more advanced a
fibrotic disease, the higher the density of fibers in the diseased
organ. Fibrotic pathology occurs in a large number of diseases,
from lung and liver fibrosis, to cardiac and cystic fibrosis,
pancreatic fibrosis, muscular dystrophy, bladder and heart
diseases, and myelofibrosis, in which fibrotic structures replace
bone marrow. Fibrotic development is attendant in several cancers,
such as breast cancer. A different pathology development is seen in
prostate cancer, where the disease destroys healthy organized
fibrous tissue. In all cases, textural spacings highlighted in the
tissue change in response to disease progression, as collagen
fibers form along underlying tissue structures. In liver disease,
the textural wavelength changes as the healthy tissue texture in
the liver is replaced by a longer wavelength texture originating
from the collagen "decoration" of the lobular structure in the
organ. In other organs/diseases, textural change reflects the upset
in healthy tissue with development of texture indicative of
fibrotic intervention.
To span the range of disease progression in most fibrotic
pathologies, evaluation of textural changes from fibrotic
development requires resolution on the scale of tenths of a mm One
of the most prevalent of such pathologies, liver disease, is
representative of the difficulty of assessing fibrotic structure.
Currently, the gold standard for pathology assessment is tissue
biopsy--a highly invasive and often painful procedure with a
non-negligible morbidity--and mortality--risk (patients need to
stay at the hospital for post-biopsy observation for hours to
overnight), and one that is prone to sampling errors and large
reading variation. (REGEV, A.; "Sampling error and intraobserver
variation in liver biopsy in patients with chronic HCV infection";
American Journal of Gastroenterology; 97, 2002. BEDOSSA, P. et al.;
"Sampling variability of liver fibrosis in chronic hepatitis C";
Hepatology, Vol. 38, issue 6, 2004. VAN THIEL, D. et al.; "Liver
biopsy: Its safety and complications as seen at a liver transplant
center"; Transplantation, May 1993.) Ultrasound, another modality
often used to assess tissue damage in liver disease, is only able
to provide adequate assessment in the later stages of the
disease--it is used to diagnose cirrhosis. Magnetic Resonance-based
Elastography (MRE), which has been under development for some time
for use in assessment of liver disease, is not capable of
early-stage assessment--the read errors are too large prior to
significant fibrotic invasion (advanced disease). Further, this
technique requires expensive additional hardware, the presence of a
skilled technician, and takes as much as 20 minutes total set up
and scanning time, making it a very costly procedure. The ability
to image fibrotic texture directly by MR imaging is compromised
both by patient motion over the time necessary to acquire data and
by lack of contrast between the fibers and the surrounding tissue.
Even acquisition during a single breath hold is severely
compromised by cardiac pulsatile motion and noncompliance to breath
hold, which results in significant motion at many organs, such as
liver and lungs. And SNR is low enough that motion correction by
combining reregistered MR-intensity profiles obtained from
successive echoes is extremely problematic. Similarly, assessment
of the amount of cardiac fibrosis in early stage disease using MRI
is seriously hampered by cardiac pulsation over the time of the
measurement. As motion is, unlike Gaussian noise, a non-linear
effect, it can't be averaged out--there must be sufficient signal
level to allow reregistration before averaging for electronic
noise-reduction. A more sensitive (higher SNR), non-invasive
technique, capable of assessing textural changes throughout the
range of fibrotic development, from onset to advanced pathology, is
needed to enable diagnosis and monitoring of therapy response.
Onset and progression of a large number of neurologic diseases are
associated with changes in repetitive fine neuronal and vascular
structures/textures. However, ability to assess such changes in the
brain is only available post mortem. Currently, definitive
diagnosis of Alzheimer's Disease (AD) is by post mortem histology
of brain tissue. AD and other forms of dementia such as Dementia
with Lewy Bodies, motor diseases such as Amyotrophic Lateral
Sclerosis (ALS), Parkinson's disease, conditions precipitated by
Traumatic Brain Injury (TBI) such as Chronic Traumatic
Encephalopathy (CTE), as well as those caused by other pathologies
or trauma, or conditions that involve damage to brain structures
such as Multiple Sclerosis (MS), Cerebrovascular Disease (CVD), and
other neurologic diseases, are often only diagnosable in advanced
stages by behavioral and memory changes, precluding the ability for
early stage intervention. Further, conditions such as epilepsy and
autism have been associated with abnormal variations in fine
neuronal structures, which, if clinically diagnosable, would allow
targeted selection for testing therapy response.
Various in vivo diagnostic techniques are available for AD and
other dementias, but none of them are definitive. These techniques
range from written diagnostic tests, which are prone to large
assessment errors, to PET imaging to assess amyloid plaque density
or glucose metabolism (FDG PET). As discussed previously, PET
imaging is extremely expensive, cannot provide high resolution, and
relies on use of radioisotopes and positioning x-ray beams,
complicating approval for longitudinal use due to dose concerns.
Further, neither amyloid imaging nor FDG PET has been shown to
provide a definitive indication of AD. (MOGHBEL, M. et al. "Amyloid
Beta imaging with PET in Alzheimer's disease: is it feasible with
current radiotracers and technologies?"; Eur. J. Nucl. Med. Mol.
Imaging.)
Use of CSF biomarkers for dementia diagnosis is painful and highly
invasive and cannot differentiate signal levels by anatomic
position in the brain, as is possible with imaging biomarkers. As
various forms of dementia are found to have different
spatial/temporal progression through the brain, this is a serious
drawback to use of liquid biopsy. Another disease associated with
various forms of dementia is CVD (Cerebrovascular Disease), which
induces cognitive impairment as a result of reduced blood flow
through blocked vessels leading to brain tissue. Something capable
of high-resolution assessment of pathology-induced changes in
micro-vessels is needed here.
Tissue shrinkage due to atrophy in many forms of dementia including
AD is measurable with careful registration of
longitudinally-acquired data in MRI, but the disease is advanced by
the time this shrinkage is measurable. Early stages of disease are
indicated in post mortem histology by degradation in the columnar
ordering of cortical neurons, the normal spacing for these columns
being on the order of 100 microns in most cortical regions.
(CHANCE, S. et al.; "Microanatomical correlates of cognitive
ability and decline: normal ageing, MCI, and Alzheimer's disease";
Cerebral Cortex, August 2011. E. DI ROSA et al.; "Axon bundle
spacing in the anterior cingulate cortex of the human brain";
Journal of Clinical Neuroscience, 15, 2008.) This textural size,
and the fact that the cortex is extremely thin, makes speed of
acquisition paramount, as even tiny patient motion will make data
collection impossible. Assessment of textural changes on the order
of tens of microns is extremely problematic in vivo, but would, if
possible, enable targeting a range of fine textural changes in
neuronal disease diagnosis and monitoring, and would play an
important role in therapy development.
Another possible neurologic application for the claimed method is
to, in vivo, determine the boundaries of the various control
regions of the cerebral cortex or the different Brodmann's areas of
which these are comprised. Such ability would greatly aid data
interpretation in brain function studies, such as those performed
using, for example, FMRI (Functional Magnetic Resonance
Imaging).
The three classes of diseases listed above, bone disease, fibrotic
diseases, and neurologic diseases are not an all-inclusive list.
Other disease states in which pathology-induced changes of fine
structures occur, for instance angiogenic growth of vasculature
surrounding a tumor, or fibrotic development and changes in
vasculature and mammary gland ducting in response to breast tumor
development, also are pathologies wherein the ability to resolve
fine tissue textures would enable early detection of disease, and
monitoring of response to therapy.
The ability to measure changes in fine textures would be of great
value for disease diagnosis. Non-invasive techniques that do not
rely on use of ionizing radiation or radioactive tracers allow the
most leeway for early diagnosis and repeat measurement to monitor
disease progression and response to therapy. Magnetic Resonance
Imaging (MRI), which provides tunable tissue contrast, is just such
a non-invasive technique, with no radiation dose concerns. However,
in order to circumvent the problem of signal degradation due to
patient motion, data must be taken on a time scale not previously
possible.
SUMMARY OF THE INVENTION
The embodiments disclosed herein provide a method for pathology
assessment employing tissue texture using magnetic resonance (MR)
which may be used integrally with an MR imaging technique. A
contrast mechanism is selected for enhancing the contrast between
component tissue types in a multiphase biologic sample for
measurement with a MR imaging process. The selected contrast
mechanism is then applied and a volume of interest (VOI) is
selectively excited employing a plurality of time varying radio
frequency signals and applied gradients. An encoding gradient pulse
is applied to induce phase wrap to create a spatial encode for a
specific k-value and orientation, the specific k-value determined
based on texture within the VOL A series of gradients is initiated
to produce k-value encodes, a resulting k-value set being a subset
of that required to produce an image of the VOL Multiple sequential
samples of the NMR RF signal encoded with the k-value set are
recorded. Post processing the recorded NMR signal samples is
accomplished to produce a data set of signal vs k-values for
k-values in the k-value set, to characterize textural features of
tissue in the VOL The MR imaging process is then performed as an
integral or hybrid pulse sequence with the texture measurement.
BRIEF DESCRIPTION OF THE DRAWINGS
The features and advantages of embodiments disclosed herein will be
better understood by reference to the following detailed
description when considered in connection with the accompanying
drawings wherein:
FIG. 1 is a simulation showing the number of data samples required
for averaging to achieve an output SNR.gtoreq.20 dB as a function
of input SNR;
FIG. 2 is a simulation showing the number of data samples needed
for averaging to achieve a SNR.gtoreq.20 db as a function of
location in k-space;
FIG. 3 is an example timing diagram of a pulse sequence for the
claimed method showing the timing of a single TR;
FIG. 4 is a close-up of the example timing diagram of FIG. 3;
FIG. 5 is an example of a timing diagram for the claimed method,
designed to acquire multiple measures of a select set of k-values,
with a different number of samples acquired at each k-value to
counteract the decrease in energy density at increasing
k-value;
FIG. 6 is a simulation showing that the ability provided by the
claimed method to acquire many repeats of signal at each targeted
k-value within a single TR enables robust signal averaging to boost
SNR;
FIG. 7 is a simulation showing the results of attempting to acquire
90 samples for averaging using the conventional frequency-encoded
echo approach, wherein acquisition of signal at only a small number
of repeats of a particular k-value are possible in each TR due to
the long record time for each echo;
FIG. 8 is an example timing diagram for the claimed method designed
to provide data acquisition over multiple refocused echoes within a
single TR; and,
FIGS. 9 and 10 are a depiction of two possible shapes for the
acquisition volume of interest (VOI);
FIG. 11 is an example timing diagram of a pulse sequence for the
claimed hybrid method showing the timing of a single TR;
FIG. 12 is a detailed view of the hybrid elements of the method at
an expanded scale;
FIG. 13 is a further detailed view of the very-low SNR acquisition
mode portion of FIG. 12;
FIG. 14 is a further detailed view of the low SNR acquisition
portion of FIG. 12;
FIG. 15 is a further detailed view of the high SNR acquisition
portion of FIG. 12;
FIG. 16 is an example timing diagram of a pulse sequence for the
claimed hybrid method showing data acquisition in a single
echo;
FIG. 17 is a further detailed view of the very-low SNR, low SNR and
high SNR acquisition portions of FIG. 16;
FIG. 18 is an example timing diagram of a pulse sequence for a low
SNR acquisition;
FIG. 19 is a further detailed view of the low SNR acquisition mode
of FIG. 18;
FIG. 20 is an example timing diagram of a pulse sequence for high
SNR acquisition;
FIG. 21 is a further detailed view of the high SNR acquisition mode
of FIG. 20;
FIGS. 22A and 22B are pictorial representations of healthy and
osteoporotic bone structure;
FIG. 23 is a pictorial representation of fibrotic tissue in a
liver;
FIG. 24 is an example timing diagram of a pulse sequence
implementing a first diffusion contrast;
FIG. 25 timing diagram of a pulse sequence implementing a second
diffusion contrast;
FIG. 26 is a pictorial representation of VOIs dispersed in fibrotic
tissue;
FIG. 27 is a pictorial representation of cortical minicolumns in
the brain;
FIG. 28 is a pictorial representation of VOI placement in the
brain;
FIGS. 29A-29C are representations of three histology images showing
progressive pathology with AD advancement;
FIG. 30 is exemplary representation of placement of a VOI in the
brain cortex and application of gradients for k-value;
FIG. 31 is a flow chart demonstrating
FIG. 32 is a flow chart demonstrating procedural flow using scout
acquisitions; and,
FIGS. 33A and 33B are a flow chart demonstrating work flow for
calibration of texture characterization for application in
diagnosis of targeted diseases.
DETAILED DESCRIPTION OF THE INVENTION
The following definition of terms as used herein is provided:
180.degree. inversion pulse RF pulse that inverts the spins in a
tissue region to allow refocusing of the MR signal. 180.degree.
pulse An RF pulse that tips the net magnetic field vector
antiparallel to B.sub.0 90.degree. pulse An RF pulse that tips the
net magnetic field vector into the transverse plane relative to
B.sub.0 3 T 3 Tesla A/D Analog to digital converter AD Alzheimer's
Disease ADC Average diffusion coefficient measured in Diffusion
Weighted Imaging Adiabatic pulse excitation Adiabatic pulses are a
class of amplitude- and frequency-modulated RF-pulses that are
relatively insensitive to 6 inhomogeneity and frequency offset
effects. ASL Arterial Spin Labelling AWGN Additive White Gaussian
Noise Additive white Gaussian noise (AWGN) is a basic noise model
used in Information theory to mimic the effect of many random
processes that occur in nature. BPH Benign Prostatic Hyperplasia
Biopsy A biopsy is a sample of tissue extracted from the body in
order to examine it more closely. BOLD Blood Oxygenation Level
Dependent C/N Contrast to Noise, a measure of image quality based
on signal differences between structural elements rather than on
overall signal level CAWGN Complex-valued, additive white Gaussian
noise CBF Cerebral Blood Flow Chemical shift Small variations in MR
resonant frequency due to the different molecular environments of
the nuclei contributing to an MR signal. CJD Creutzfeld-Jakob
Disease Crusher gradients Gradients applied on either side of a
180.degree. RF refocussing slice selection pulse to reduce spurious
signals generated by imperfections in the pulse. CSF Cerebrospinal
fluid CVD Cerebrovascular disease DCE Dynamic Contrast Enhanced
DEXA Dual Energy X-ray Absorptiometry is a means of measuring bone
mineral density using two different energy x-ray beams. DSC Dynamic
susceptibility contrast DTI Diffusion Tensor Imaging DWI Diffusion
Weighted Imaging Echo The RF pulse sequence where a 90.degree.
excitation pulse is followed by a 180.degree. refocusing pulse to
eliminate field inhomogeneity and chemical shift effects at the
echo. Frequency encodes Frequency-encoding of spatial position in
MRI is accomplished through the use of supplemental magnetic fields
induced by the machine gradient coils Gaussian noise Gaussian noise
is statistical noise having a probability density function (PDF)
equal to that of the normal distribution, which is also known as
the Gaussian distribution. Gradient pulse a pulsing of the machine
magnetic field gradients to alter the k-value encode Gradient set
the set of coils around the bore of an MR scanner used primarily to
spatially encode signal or to set a particular phase wrap in a
selected direction GRE Gradient Recalled Echo Interleaved
acquisition Signal acquisition from a multiplicity of VOIs,
successively excited within a single TR Isochromat A microscopic
group of spins that resonate at the same frequency. k-space The 2D
or 3D Fourier transform of the MR image. k-value coefficient The
coefficient in a Fourier series or transform reflecting the
relative weight of each specific k-value in the series. k-space The
2D or 3D Fourier transform of the MR image. k-value One of the
points in k-space reflecting the spacing of structural elements in
a texture field. k-value selection pulse The gradient pulse used to
select a specific k-value encode along the sampled direction
Library of k-space values the net collection of k-space
coefficients acquired in a particular region of tissue for tissue
characterization Machine gradients the magnetic field gradients
imposable through use of the set of gradient coils in an MR scanner
MRE Magnetic Resonance Elastography--an imaging technique that
measures the stiffness of soft tissues using acoustic shear waves
and imaging their propagation using MRI. MRI Magnetic Resonance
Imaging MRS Magnetic Resonance Spectroscopy MS Multiple Sclerosis
MTI Magnetization Transfer Imaging Noise floor In signal theory,
the noise floor is the measure of the signal created from the sum
of all the noise sources and unwanted signals within a measurement
system NMR Nuclear Magnetic Resonance PET Positron Emission
Tomography is a functional imaging technique that produces a
three-dimensional image of functional processes in the body using a
positron-emitting radiotracer. Phase coherence (spatial) When
referring to multiple measurements within a common VOI of a or
multiple k-values indicates that the sample has the same position
relative to the measurement frame of reference Phase encode A phase
encode is used to impart a specific phase angle to a transverse
magnetization vector. The specific phase angle depends on the
location of the transverse magnetization vector within the phase
encoding gradient, the magnitude of the gradient, and the duration
of the gradient application. Phase wrap The helical precession of
the phase of the transverse magnetization along a phase encoded
sample Pitch with reference to the pitch of a screw, the tightness
of the phase wrap along the direction of k-value encode Profile A
one dimensional plot of signal intensity RF Radio Frequency
electromagnetic signal Semi-crystalline texture a texture
exhibiting regular spacing along one or more directions slice
(slab) Used interchangeably to indicate a non-zero thickness planar
section of the Slice-selective refocusing Refocussing of spins
through combination of a slice selective gradient and an RF pulse
such that the bandwidth of the RF pulse selects a thickness along
the direction of the gradient, and the RF pulse tips the net
magnetization vector away from its equilibrium position Only those
spins processing at the same frequency as the RF pulse will be
affected. SE Spin Echo SNR Signal to Noise Ratio Spoiler gradients
see crusher gradients T2 Defined as a time constant for the decay
of transverse magnetization arising from natural interactions at
the atomic or molecular levels. T2* In any real NMR experiment, the
transverse magnetization decays much faster than would be predicted
by natural atomic and molecular mechanisms; this rate is denoted
T2* ("T2-star"). T2* can be considered an "observed" or "effective"
T2, whereas the first T2 can be considered the "natural" or "true"
T2 of the tissue being imaged. T2* is always less than or equal to
T2. TBS Trabecular Bone Score is a technique that looks for texture
patterns in the DEXA signal for correlation with bone
microarchitecture for assessing bone health TbTh trabecular
thickness for bone measurement. TbSp trabecular spacing for bone
measurement. TbN trabecular number for bone measurement. TE Spin
Echo sequences have two parameters: Echo Time (TE) is the time
between the 90.degree. RF pulse and MR signal sampling,
corresponding to maximum of echo. The 180.degree. RF pulse is
applied at time TE/2. Repetition Time is the time between 2
excitations pulses (time between two 90.degree. RF pulses).
Textural frequency the number of texture wavelength repeats per
unit length in a texture Texture wavelength the characteristic
spacing between structural elements in a texture TR Spin Echo
sequences have two parameters: Echo Time (TE) is the time between
the 90.degree. RF pulse and MR signal sampling, corresponding to
maximum of echo. The 180.degree. RF pulse is applied at time TE/2.
Repetition Time is the time between 2 excitations pulses (time
between two 90.degree. RF pulses). Vector combination gradient A
magnetic gradient resulting from any vector combination of the
gradient coil set VOI Volume of Interest Windowing function In
signal processing, a window function (also known as an apodization
function or tapering function) is a mathematical function that is
zero-valued outside of some chosen interval x-ray diffraction X-ray
diffraction is a tool used for identifying the atomic and molecular
structure of a crystal
The embodiments disclosed herein provide an MR-based technique that
enables in vivo, non-invasive, high-resolution measurement and
assessment of fine biologic textures, enabling monitoring of
texture formation and/or change in response to disease onset and
progression in a range of pathologies. This same method can be
applied to fine-texture characterization in other biologic and
physical systems. It enables MR-based resolution of fine textures
to a size scale previously unattainable in in vivo imaging.
In standard MR "imaging" the morphology of a large region of
anatomy or an organ is imaged by using a pulse sequence that
induces contrast from one tissue type/organ to the next. To obtain
an image, signal must be averaged over individual voxels, the size
of the voxels then setting the image resolution.
This imaging will be sensitive to tissue contrast near lesions,
such as tumors, etc. that appear then at localized points of an
organ in the image. Or, the image might show that an organ has
changed, perhaps become enlarged, relative to a healthy organ. As
such, the basic image is the anatomy and any localized pathology
shows up on this anatomical image.
To acquire a 3D image, data acquisition can be by acquisition of
multiple, spatially adjoining, slices, or as a 3D dataset directly.
In effect, a 2D slice is a "map" of signal level, the individual
pixels of the map being the individual voxels. The signal level of
each voxel depends on the contrast mechanism applied. The relative
signal levels of each voxel then form the image. Though, in effect,
this is a map of voxel brightness, when the intent is to depict
morphologic variation directly across a region of the anatomy, it
is called an image.
Alternatively, mapping is the creation of a display of an indirect
quantity that affects the brightness of an MR signal. It is not a
map of morphology, but of an inferred tissue characteristic, such
as Apparent Diffusion Coefficient, or Fractional Anisotropy, or
organ stiffness. As such, the brightness in the voxels that make up
the mapped quantity also form an "image" but in common usage this
would be called a map. Often such a map is compared to an image
from the same anatomical region. This would allow, for instance, a
tumor region that shows up bright on, say, the brain in an image,
to be compared to the diffusion coefficient in that region.
The terms imaging and mapping may be used interchangeably in the
description herein and refer to a resulting dataset for display or
manipulation not necessarily an attempted reproduction of a
"picture" image of the morphology.
The method, while described herein with respect to biological
systems for examination of tissue, is equally applicable for
assessment of fine structures in a range of industrial purposes
such as measurement of material properties in manufacturing or in
geology to characterize various types of rock, as well as other
uses for which measurement of fine structures/textures is
needed.
The embodiments disclosed herein achieve this significant
improvement in in vivo resolution of fine texture by acquiring the
requisite data fast enough that the effect of subject motion, the
factor that limits MRI resolution, becomes negligible. This fast
acquisition is achieved by acquiring data incrementally--at a
single location, orientation and at one, or a select set or range,
of k-values at a time--within one TR, if multiple pulses are used,
or within one excitation pulse. After applying an encoding gradient
to select the k-value of interest, data is acquired with the
gradient switched off, allowing multiple acquisition repeats of the
signal at the encoded k-value for subsequent averaging to reduce
electronic noise, thus enabling robust measure at individual
k-values before motion blurring can occur. To build up measurements
on a larger set of selected k-values present within the tissue, or
towards development of a continuous spectrum of textural spacings
within the tissue, the acquisition TR can be repeated as many times
as necessary, changing the encode as needed to span the desired
extent of real and of k-space required. The set of signals measured
at one or more k-values output from each TR are now high SNR due to
the ability to average repeats without motion effects, and since
the measure of interest is textural spacing, and not development of
an image, the lack of phase coherence between TRs is of no
concern.
In its simplest form the embodiments disclosed herein consist of
acquiring MR signal from within an inner volume to encompass a
specific tissue region of interest, such as a lesion, an organ, a
location in an organ, a specific region of bone, or a number of
regions in a diseased organ for sampling. This inner volume may be
excited by one of a number of methods, including but not limited
to: intersecting slice-selective refocusing, selective excitation
using phased-array transmit in combination with appropriate
gradients, adiabatic pulse excitation to scramble signal from the
tissue outside the region of interest, outer volume suppression
sequences, and other methods of selectively exciting spins in an
internal volume including physically isolating the tissue of
interest, to name a few,
After definition of a volume of interest (VOI), in certain
embodiments, the gradient is turned off, and multiple samples of
signal centered at a specific k-value, the spread of which is
defined by receiver BW and sampling length, are acquired. This
measurement is repeated only at a set of k-values and in specified
directions within the VOI, rather than trying to map all of k-space
as is required to generate an image. One or more samples of signal
at a particular k-value are acquired within an acquisition block
during a single TR, or excitation pulse, and the k-value
subsequently incremented or decremented, allowing further samples
at other k-values as desired during the same TR, or excitation
pulse. This method allows multiple sampling at each k-value of
interest over a time period of milliseconds, providing immunity to
subject motion. The process can then be repeated in further TRs,
the requirement on motion between signal acquisitions at specific
k-values being only that the VOI remain within the tissue region of
interest. Buildup of a magnitude spectrum of textural frequencies
may be accomplished without the need to acquire it in a spatially
coherent manner Because the quantities of interest are the relative
intensities of the various k-values (textural spacings) present in
the sample volume, as long as the acquisition volume remains within
a representative sample of tissue, any motion between the blocks
does not compromise the measurement. In the case of motion of
sufficiently large magnitude that an internally excited volume
might be formed in other tissue volumes over the course of building
up a spectrum of k-values contained in the tissue, use of fairly
robust, real-time piloting and acquisition algorithms can be used
for gross repositioning of the internal selectively excited volume
and for rejecting data sets that have failed to stay in the proper
tissue.
Repositioning the VOI to allow sampling of texture at multiple
positions within or across an organ or anatomy allows determination
of the variation in pathology through the organ. The data acquired
can, with reference to positioning images, be mapped spatially.
Either the VOI can be moved in successive TRs or interleaved
acquisition done within a single TR by exciting additional volumes
during the time that the signal is recovering in advance of the
next TR. The requirement is that successive VOIs be excited in new
tissue, that does not overlap the previous slice selects. Spatial
variation of pathology can be determined by this method. This can
also be used to monitor temporal progression of a pathology through
an organ if the measure is repeated longitudinally.
Tailoring the pulse sequence to pre-wind phase in the sample volume
can position the measure of signal at the highest k-values of
interest at the echo peak where the signal is strongest, providing
best SNR measurement.
Sampling of signal at k-values, with the acquisition axis oriented
along varying directions, aligned at varying angles and along
varying paths, either rectilinear or curved, within the volume(s)
under study can yield important information on texture, especially
textures with semi-ordered structure in specific directions, such
as neuronal minicolumns. Measurement of signal vs. k-values
associated with columnar spacing is extremely sensitive to
alignment of the sampling path, as slight variations in sampling
direction on either side of perpendicular show a rapid drop off in
signal for that k-value. Rocking the acquisition path on either
side of the signal maximum can yield a measure of pathology-induced
randomness which is indicated by the width of the signal vs.
k-value peak.
With the gradient switched off for data acquisition, tuning the
bandwidth to particular chemical species can enhance structural
information when the chemical composition of the structure under
study is known.
The embodiments disclosed herein can be used in conjunction with
time-dependent contrast schemes that target blood flow. Some of
these contrast techniques are Blood Oxygenation Level Dependent
(BOLD) imaging, Arterial Spin Labeling (ASL) imaging, and Dynamic
Susceptibility Contrast (DSC) imaging. As these methods use various
techniques to highlight vasculature, changes in the texture of the
vasculature associated with many pathologies, including CVD
(cerebrovascular disease) and tumor growth can be measured.
The embodiments disclosed herein can also be used in conjunction
with various novel MR-contrast mechanisms, including DWI, DTI and
MTI, to provide front end information toward parameter selection
for the diffusion techniques as well as correlation with their
measurements of tissue health.
The rapid repeat measurement of signal at a single k-value, with
the total time to acquire a block being on the order of a msec,
reduces patient and machine motion-induced blurring to a negligible
level, enabling robust assessment of fine textures previously not
accessible in vivo. (For comparison, standard MR image acquisition
times are much longer in duration over which patients are asked to
remain completely stationary.) Since the excited tissue defining
the VOI moves with any tissue motion, acquisition within one TR, or
excitation pulse, is largely immune to subject motion. The SNR of
signal measured at each k-value selected is significantly improved
through combination of the individual samples at each k-value
within a block; this averaging can be done without concern for
subject motion, which is eliminated due to the rapid sequential
acquisition of the individual samples in the block.
This significant improvement in SNR is made possible because the
embodiments disclosed herein focus on acquiring signal at only the
k-values of interest for determination of fine texture pathology
signatures, rather than on acquisition of the large number of
spatially-encoded echoes required for image formation. The
significantly reduced data matrix enables the increased number of
coherent repeats at the targeted k-values, and hence significant
improvement in SNR.
Energy density within a range of textural spacings is proportional
to textural wavelength, or inversely to k-value--i.e. the higher
the k-value, the lower the associated signal intensity. The fast
acquisition enabled through use of the embodiments disclosed
herein, enables tailoring the number of acquisition repetitions at
a particular k-value to acquire k-values for which there is low
signal first, before T.sub.2 and T.sub.2* effects have degraded
signal amplitude. In this way, the SNR of each repeat to be
averaged for noise cancellation (or spatial-phase-corrected before
combining it with the measurements of k-value from subsequent TRs)
will be above this threshold. It does not matter that there is
motion between acquisition cycles at different k-values as long as
each acquisition lies within the tissue volume of interest (VOI).
As the claimed method targets only assessment of pathology-induced
changes in tissue texture, there is no requirement for phase
coherence over an entire cycle of data acquisition, as is required
in imaging.
Several benefits result from acquiring data after the gradient is
switched off for single-k-value sampling in a reduced volume (the
VOI). By proper pulse sequencing, the echo record window can be
designed such that recording begins with the highest k-values of
interest, as signal level is highest at the echo peak. This enables
recording of fine structures currently unachievable with in vivo MR
imaging.
Additionally, T2* is longer with the gradient off, so SNR is
improved by the longer acquisition times possible. This allows
acquisition of an increased number of samples, N.
Coil combination is also simplified by having higher SNR for each
k-value, hence providing a significant improvement in overall SNR.
This is especially beneficial as the trend in MRI is towards coil
arrays composed of many small element coils. As the acquisition
volumes targeted in the embodiments disclosed herein are small,
correction for phase across the sample volume is not needed. Only
one phase and gain value for each coil is needed for combining the
multiple element channels. These can be combined using the Maximal
Ratio Combining (MRC) method, which weights the coil with the
highest SNR most heavily, or other multi-signal combination
methods. (Phase and gain for the elements of a given coil array can
be determined once from a phantom and applied to patient data.)
Signal acquisition and data sampling in a standard MRI scan is done
by acquiring complex-valued samples of multiple echoes, while
applying a gradient sequence concurrently, as well as in sequence
with the echoes. Imaging relies on frequency encode for one of the
dimensions because this allows a line in k-space to be acquired
with each phase encode rather than a single point. For
3-dimensional imaging, two dimensions in k-space normally rely on
phase encode to generate the targeted filling of k-space, with the
third dimension frequency-encoded. Phase encode acquisition in
imaging usually entails acquisition of on the order of 256 k-values
in each of the phase-encode directions, hence is a relatively slow
process. Clinical MRI scans take on the order of 10-15 minutes to
generate an image. The aim in image construction is to acquire
sufficient k-space coverage to fill out all the coefficients in the
2 or 3-dimensional Fourier series, which is why in standard MR
resolution is limited by subject motion.
The embodiments disclosed herein is in direct contrast to standard
MR data acquisition, with its focus on image generation Image
formation is plagued by blurring resulting from subject motion over
the long time necessary to acquire the large data matrix required.
Since the target of the embodiments disclosed herein is texture
rather than image, the only requirement on subject motion is that
the sampled volume remain within a region of similar tissue
properties over the course of acquiring data. This is a much less
stringent and easy to achieve target than the requirement of
structural phase coherence, as the scale of the allowable motion is
then large enough, and of a temporal order, to be easily
correctable by real-time motion assessment and correction
techniques. The speed of acquisition for the embodiments disclosed
herein is such that, in most cases, real-time motion correction may
not be necessary at all. While other methods have focused on
post-processing of images to try to extract textural measures, the
embodiments disclosed herein eliminates the need for image
generation, focusing instead on directly measuring texture, hence
enabling a more sensitive and robust measure.
Frequently, k-space sampling is considered synonymous with sampling
of an echo in the presence of a gradient set. In certain
embodiments disclosed herein, the approach to k-space filling is to
acquire only the set of k-values needed for texture evaluation in
the targeted pathology, with data acquired after the gradient is
switched off. This method enables such rapid acquisition of
single-k-value repeats for averaging for noise reduction that
subject motion does not degrade the data.
Along with the huge improvement in SNR that arises from sampling
k-values individually, with many repeats of a select set of
k-values acquired in a single TR, or single excitation pulse,
acquisition after the gradient is switched off allows further
significant improvement in SNR and hence, increase in measurement
robustness. This is explained in the following discussion.
These same benefits of improved SNR can be achieved with the
gradient ON during signal acquisition, allowing acquisition across
an evolving range of k-values, as long as the gradient is low
enough. Signal can be acquired in the presence of a low gradient
used to provide specified trajectory across a small range in
k-space during data acquisition.
MR echo sampling provides specific samples vs. time of a
time-dependent echo. The echo is comprised by the gradients applied
concurrently (for the frequency-encode axis) and prior to (for a
phase encode axis), but also contains the isochromats associated
with the different chemical species of the sample, as well as the
envelope (T2 & T2*) associated with spin-spin interactions.
Conventional frequency-encoded spin acquisitions impose a
time-varying gradient upon the sample, which effectively travels in
k-space along a pre-defined path. For rectilinear sampling, the
path is along a straight line.
Frequency encodes generate only one measurement at a given
k-value--at a given point in time, the acquired sample of the echo
represents the one value which corresponds to the Fourier
coefficient at a specific k-space location. The next echo sample
represents the value at a different k-space location, the next
k-value dependent on the slope of the gradient applied
concurrently. As long as there is sufficient signal at the
corresponding k-value, this approach works well. However, in cases
where the signal of interest is near or even below the noise floor,
usually additional samples and subsequent post-processing will be
required.
One way to reduce the noise floor in a frequency-encoded gradient
read-out is to reduce the gradient strength and lower the receiver
bandwidth. Decreasing the receiver bandwidth will indeed decrease
the noise level, and improve lower signal level detection
(proportional to the term k.sub.B TB, with k.sub.B corresponding to
Boltzmann's constant, T corresponding to Temperature in Kelvin, and
B is the receiver bandwidth in Hz.) However, this comes at the
expense of larger chemical shift artifacts.
Chemical shift artifacts arise as a consequence of the different
isochromats associated with different chemical species within the
biological sample. In a frequency-encoded k-space read-out, those
chemical species which resonate at a slightly higher frequency will
appear to be displaced from their actual location in image space
towards the direction of increasing frequency. If the spatial
frequency encoding gradient is shallow, the apparent displacement
can be quite large.
As such, to minimize chemical shift artifacts, the gradient slope
is typically made as steep as possible to minimize the apparent
shift to within a narrow range (i.e. within 1 or two pixels in the
image domain). However, this then requires a larger receiver
bandwidth to accommodate the larger frequency range. This in turn
increases the overall noise floor at a level proportional to the
receive bandwidth.
The conclusion is that frequency readouts generally force a
trade-off between gradient strength, noise level, and chemical
shift artifacts.
A common technique for noise reduction in signal acquisition is
through repeat sampling of a signal and subsequent combination of
the multiple measurements. For linear noise sources, such as
Gaussian noise, this technique improves SNR through cancellation of
the random noise on the signal, the cancellation effect increasing
with the number of samples, N.
Noise reduction by this cancellation technique works for static
subjects. However, motion-induced blurring is a non-linear effect,
so signal combining for which the individual measurements have
shifted through large spatial phase angles (relative to the
textural/structural wavelengths under study) does not lead to an
improved SNR. A fairly standard technique to correct for motion is
to look at the MR intensity data in real space and reregister
successive traces/images to each other to maximize overlap. It is
assumed that, as with the reduction in white noise, linear
combination of these reregistered signals will result in reduction
of the blurring caused by the motion. However, this only works if
the SNR on each individual acquisition is high enough.
Reregistering low SNR samples results in a high variance in the
estimated position. Threshold theory defines that combining
reregistered signals with non-linear blurring, when the original
signals are below a certain noise threshold, only increases signal
error.
The nonlinearity introduced by subject motion increases at higher
k-values, since the motion-induced textural phase shift increases
with k--i.e. as the size of the structures of interest decrease,
the adverse consequence of motion become more acute. This implies
that the multiple samples to be combined need to be derived from
the same acquisition sequence, acquired in a sufficiently short
time span, to ensure there is negligible motion between
samples.
The Cramer-Rao Lower Bound provides insight into the number of
samples that are required for a lower bound on the residual
variance of an estimate, i.e. the SNR vs. number of samples, in
Additive White Gaussian Noise (AWGN). For low source SNRs in AWGN,
one needs a large number of samples to average in order to obtain a
usable SNR. The primary assumption is that multiple acquisitions
can be taken, then averaged to achieve the higher SNR. (CRAMER, H.;
"Mathematical Methods of Statistics"; Princeton University Press,
1946. RAO, C. R., "Information and the accuracy attainable in the
estimation of statistical parameters"; Bulletin of the Calcutta
Mathematical Society 37, 1945.)
Referring to the drawings, the graph in FIG. 1 comparing output SNR
shown in trace 102 with number of samples required shown in trace
104 demonstrates that, for high input SNRs, a single sample is
sufficient to yield a low noise measure. For lower SNRs, multiple
samples are required to "average out" the noise contribution. The
ability to combine the samples explicitly assumes that the
underlying signal of interest is relatively constant during the
multiple sample acquisition process (i.e. the only component which
changes is the noise).
The graph in FIG. 2 is a simulation with signal model, trace 202,
providing an input SNR, trace 204, showing number of samples of
k-value, trace 206, needed to yield a SNR of 20 dB as a function of
location in k-space, given an input noise level of 3 mV rms. Since
spectral energy density is generally proportional to k.sup.-1, to
maintain adequate SNR a larger number of input samples is required
at higher spatial frequencies (higher k-values). The noise level
for the simulation is adjusted for .about.10 dB SNR at k=2
cycles/mm (.lamda.=500 .mu.m).
As pointed out above, this type of averaging is possible for purely
static samples with no displacement or deformation of the targeted
tissue occurring over the temporal span of data acquisition.
However, for in vivo applications, natural motion occurs even if
the patient is compliant. As the texture spacing of interest
decreases, the adverse consequences of motion become more acute.
More to the point, this type of averaging is based upon the
assumption that the underlying signal is the same across
acquisitions, and that only the zero-mean, complex-valued,
additive, white Gaussian noise (CAWGN) changes. If the signal
itself changes, the result will be an average, not only of the
noise, but also of the N different versions of the underlying
signal, which really doesn't improve SNR.
Using low SNR samples to estimate and correct for motion will
result in a high variance of the estimated position. This in turn
yields a large variance in the "corrected" acquisitions and does
not yield the anticipated increase in SNR when these acquisitions
are averaged. This implies that the multiple samples need to be
derived from the same acquisition sequence, where motion between
samples is extremely small. This is enabled by the embodiments
disclosed herein.
The issue becomes more acute with shorter structural wavelengths.
Consider two acquisitions, noise-free for the moment, one of which
has been displaced by an amount d. For a given k-value, an attempt
to average them produces: Y(2.pi.k):=S(2.pi.k)[1+e.sup.-j2.pi.kd]/2
(0.1) Where S(2.pi.k) the complex-valued signal, and Y(2.pi.k)
represents the average of the two acquisitions.
This can be expressed as: Y(2.pi.k):=S(2.pi.k)e.sup.-j.pi.kd
cos(.pi.kd) (0.2)
Which shows both a magnitude attenuation and phase shift, due to
the displacement d. Limiting the magnitude attenuation to a floor
value a, where 0<a<1, limits d to:
.ltoreq..function..pi..times..times. ##EQU00001##
This shows that, for a given magnitude error, the allowable
displacement decreases with increasing values of k. This is
because, the smaller the textural spacing of interest, the less
motion can be tolerated over the course of data acquisition.
To deal with this problem, an alternate approach is taken in the
embodiments disclosed herein, which is to dispense with the
frequency-encoded readout and to sample specific k-space points,
acquiring one or multiple measurements at each k-value of interest
at a single spatial location and orientation at a time.
Within a given acquisition in standard MR practice, there are M
samples which are acquired of the echo. Instead of acquiring a
sample at each k-value, N.ltoreq.M of those samples could be used
for estimation of the (complex-valued) underlying signal value at a
specific k-value. Multiple samples within an acquisition can be
combined with much less concern of movement than across
acquisitions because they are much closer in time.
If the entire echo is used to measure one k-value, the receive
bandwidth can be adjusted so as to pass the most abundant resonant
peaks in the underlying NMR spectrum, and attenuate frequencies
above them.
Taking a straight MRS spectrum (no structural phase encodes), would
yield a spectrum consisting primarily of peaks corresponding to
H.sub.2O (with a chemical shift of .delta.=4.7 ppm), as well as
Carbon-Hydrogen bonds which occur in fat (e.g. CH3, CH2, CH.dbd.CH,
etc.), each with a different chemical shift ranging from 0.9-5.7
ppm, with the most abundant resonance coming from CH2 in the
aliphatic chain which occurs at .delta.=1.3 ppm.
Assuming use of a 3T machine, since the Gyromagnetic ratio of
Hydrogen is .gamma.=42.576 MHz/T, the chemical shift values are in
the range of 166 Hz (for CH2) to 600.3 Hz (for H2O). As long as a
(single sided) receiver bandwidth in excess of 600.3 Hz is used,
the H.sub.2O peak will pass. Assuming baseband sampling, this
implies a sampling rate >1.2 kHz (note, if complex base-band
sampling is used, this could theoretically be reduced by about
1/2.) The point here is that a narrow bandwidth can be used by this
method, and sample rates on the order of 800 .mu.s. Noise on the
signal is thereby reduced and multiple repeats of the k-value
acquisition data are acquired in milliseconds, thereby making the
acquired data immune to patient motion. For comparison, a single
imaging acquisition is made with a TE of .about.30 ms, and TR on
the order of 500 ms-2000 ms. To acquire the repeats necessary for
signal averaging can take minutes--a temporal range wherein
respiratory, cardiac, and twitching motion limits resolution
through motion-induced blurring. The claimed method enables
acquisition of values in regions of k-space which have very low
signal levels, such as would be found for higher k-values (shorter
textural-wavelengths)--the fine texture range that has hitherto
remained elusive.
To maximize the signal, the non-zero frequencies of abundance are
selected. In general, this does not correspond to a mere averaging
of all of the samples acquired. Instead it is akin to a matched
filter which is "tuned" to the frequency of interest, corresponding
to the specific chemical species of interest.
As a side note, the full NMR spectrum may be extracted (without any
phase encoding gradients: just volume selection) to obtain a
baseline of the underlying signal strength (and associated
frequencies), which in turn will be spatially modulated, providing
insight into textural wavelengths through knowledge of the chemical
species expected in the textural elements under study.
The isochromats of interest can be extracted by acquiring N samples
of the echo, then taking the Fourier transform. Since the echo is
being played out with no gradient, the strength of the resulting
signal at the Isochromat of interest will correspond to the
(complex-valued) k-value coefficient of interest.
Given the goal is to extract the relative magnitude of textural
wavelengths, just the magnitude vs. textural wavelength measurement
is the required information. However, in order to extract
sufficient signal strength and differentiate it from the underlying
noise floor, the complex phasor values must be preserved until the
end.
The relationship between the noise floor, the signal strength (at a
specific isochromat where there is an abundance of chemical
species), the number of samples required, and the max tolerated
error can be approximated as
.gtoreq..sigma..times. ##EQU00002## Where .sigma..sup.2 represents
the noise variance, |A|.sup.2 represents the squared magnitude of
the isochromat(s) of interest, and 0<.epsilon.<1 represents
the allowable error of the estimate. Further assuming that the
noise is mostly sourced from the biological sample, this can be
further approximated as:
.gtoreq..times..times. ##EQU00003## Where NF.sub.eff is the
effective noise figure of the receiver, k.sub.B is Boltzmann's
constant, T is the temperature in Kelvin of the biological sample,
and B is the receiver bandwidth. In this case, N can be used as a
guide to the number of samples that need to be acquired within a
given acquisition in order to create a reasonable estimate.
If the number of samples required exceeds the number available in
one acquisition, combination of measurements from a single
acquisition may be needed to maximize the signal, prior to spatial
reregistration between acquisitions. A reasonable estimate and
displacement correction between the two or more acquisition sets is
needed. Combination of measurements at a single k-value from a
single TR block can now be used to boost the SNR such that
reregistration between successive TRs has a much greater chance of
success.
While the entire set of samples acquired in an echo or entire TR
could be allocated to the estimate of one coefficient in k-space,
if acceptable values can be estimated using fewer than the maximum
number of echo samples, it opens up the possibility of being able
to acquire more than one coefficient in k-space within a specific
echo or TR.
Various pulse sequences are provided for exemplary implementations
of the embodiments disclosed herein. The examples may be combined
with each other and with other MR imaging techniques, in parallel
and in integrated forms, to obtain the desired micro-texture
imaging associated with investigation of diseases having various
pathologies. FIG. 3 shows an example timing diagram for a pulse
sequence for data acquisition using the embodiments disclosed
herein. RF pulses included in trace 302 are employed to excite
selected volumes of the tissue under investigation, as in typical
MR imaging. A first RF pulse, 304, is transmitted coincidentally
with a gradient pulse 308 on the first magnetic field gradient,
represented in trace 306. This excites a single slice, or slab, of
tissue the positioning of which is dependent on the orientation and
magnitude of the first gradient, and the frequencies contained in
the RF pulse. The negative gradient pulse, pulse 310, rephases the
excitation within the defined thickness of the slice or slab.
A second RF pulse 312, at twice the magnitude of first RF pulse
304, is transmitted coincidentally with gradient pulse 316, on a
second gradient, represented in trace 314, exciting a
slice-selective refocus of spins, this second tissue slice
intersecting with the first. (As this second RF pulse 312 tips the
net magnetic vector to antiparallel to B.sub.0, it results in
inversion of spins and subsequent refocusing, thus leading to a
signal echo at a time after the 180 degree RF pulse equivalent to
the time between the 90.degree. and 180.degree. RF pulses.) An
initial higher value gradient pulse, 318, at the start of gradient
pulse 316 is a crusher, or "spoiler" gradient, designed to induce a
large phase wrap across the tissue volume. A similar gradient
pulse, 322, at the trailing end of pulse 316, as it comes after the
180 degree RF inversion pulse, unwinds this phase wrap. In this
way, any excitation that is not present prior to the 180 degree RF
pulse, such as excitations from imperfections in the 180 pulse
itself, will not have this pre-encode so will not be refocused by
the second crusher, hence will not contribute to the signal. In
summary, the second RF pulse, in combination with the applied
second gradient, provides slice selective refocusing of the signal
in a region defined by the intersection of the first slice and the
second slice set by this second gradient.
An encoding gradient pulse 326, on trace 314, sets an initial phase
wrap, hence k-value encode, along the direction of gradient pulse
326. In general, the k-value encode can be oriented in any
direction, by vector combination of the machine gradients but for
ease of visualization is represented as on the second gradient.
A refocusing third RF pulse 328, applied in combination with
gradient pulse 332 on a third gradient, represented by trace 330,
defines a third intersecting slice selective refocus to define the
VOL Gradient pulse 332 again employs crusher gradients.
The negative prephasing gradient pulse 326 winds up phase such
that, at the signal echo following the second 180.degree. RF pulse,
signal acquisition starts at high k-value, which may then be
subsequently decremented (or incremented or varied in orientation)
for further acquisitions, as will be described below. As energy
density in the signal is generally proportional to k.sup.-1, this
method ensures k-values with lower SNR are acquired first, before
T.sub.2 effects have caused much overall signal reduction.
With all gradients off, a receive gate 333 is opened to receive the
RF signal, which is shown in FIG. 3 as pulse 334 on trace 336. The
RF signal in trace 336 is a representation showing only the signal
present in the receive gate window without showing the actual
details of the RF signal outside the window. Sampling occurs as
represented by trace 338 beginning with the initial k-value, 340a,
seen on trace 324. Note that, at the scale of the drawing, the
sampling rate is high enough that the individual triggers of the
analog to digital converter (A/D) have merged together in trace
338. (The expanded time scale in FIG. 4 described below shows the
individual A/D triggers.)
In regions of k-space where the corresponding coefficients are
sufficiently large that they can be well-estimated using a small
subset of the samples of one echo, acquisition of another k-value,
obtained by applying a gradient pulse 342a shown on trace 314, to
select a new k-value, during the time the echo is being recorded,
is accomplished. After a suitable settling time, another set of
samples of the echo (now derived from the new k-value coefficient)
can be collected. This process can be repeated, acquiring multiple
samples at each of a select set of k-values within one TR. A
plurality of samples are taken at the initial k-value 340a. A
k-value selection gradient pulse 342a is then applied and the
resultant k-value 340b is sampled. (Though shown in the figure as a
negative pulse on the second gradient, decrementing the k-value, in
practice this pulse and subsequent k-value gradient pulses can be
designed through any vector combination of gradients to select any
k-value or orientation.) Similarly, the k-value selection gradient
pulse 342b, selects a third k-value 340c which is sampled by the
A/D. Each gradient pulse changes the phase wrap, selecting a new
k-value. Application of a k-value selection gradient pulse
(342c-342f) followed by multiple sampling of the resultant k-value
coefficient is repeated as many times as desired. While data is
being acquired throughout, the samples of interest are acquired
when all gradients are off. The gradient orientations for slice and
k-value select may be coincident with the machine gradients, which
are aligned to lie coincident or orthogonal to the B.sub.0 field.
Alternatively, the acquisition directions and k-value encodes may
be selected using gradients that are a vector combination of all
three machine-gradient axes.
In the circumstance where it is desired to measure a low SNR
k-value the prewinding encoding gradient pulse can be set such that
the first k-value to be measured is the desired low SNR k-value.
Alternatively, the prewinding gradient pulse can be set to zero so
that the first k-value measured is k0. A measurement of k0 may be
desired for the purpose of determining the systems receiver
sensitivity to the particular VOI, determining the relative
prevalence of isochromats (e.g., water vs. lipids) irrespective of
texture in the VOI, or for the purpose of establishing a reference
value for normalization of the other k-values measured in a VOI or
for comparison with k-values from other VOL Furthermore a strategy
for gathering a specified set of k-values for a VOI may include
measuring the low SNR k-values (typically the higher k-values) in a
first set of multiple TR and then measuring k0 and other higher SNR
k-values in other TRs while remaining in the same VOI.
As is shown diagrammatically in FIG. 3, the signal reaches a
maximum at the time of the spin echo. It is also shown
diagrammatically that the signal is varying throughout the
acquisition of the multiple RF measurements of a k-value and more
so between successive blocks of measurements of k-values. Alignment
in time of the measurement of the low SNR k-values with the highest
echo signal enhances the SNR of the k-value measurement,
alternatively alignment of higher SNR k-values with lower echo
signal allows gathering additional useful k-value acquisitions
during the echo. The term k-value measurement is understood in the
art to be a "shorthand" term for measurement of signal at a
k-value.
FIG. 4 shows a close-up of the pulse sequence of FIG. 3 during the
initial portion of the RF sampling window 338 between 7.25 and 8.00
msec. Multiple samples of the same k-value, taken in rapid
succession with all gradients off, provide the input for signal
averaging to reduce AWGN when SNR is low. In a first block 344a of
the sampling window 338, multiple samples 346a are taken of the
first k-value 340a. During application of the k-value selection
gradient pulse 342a, transition samples 348a are taken. When the
k-value selection gradient is switched off, multiple samples 346b
are taken at the second k-value 340b. Application of k-value
selection gradient pulse 342b then occurs with associated
transition samples 348b, and subsequent acquisition of samples 346c
of the third k-value 340c after the gradients are switched off. The
underlying signal is minimally impacted by motion due to the very
short time window used to acquire data at each given k-value. Since
the data is acquired with gradients off, there is no issue with
chemical shift and the effective T.sub.2* is longer, boosting the
signal value.
The sampled values of the echo, acquired while the k-value
selection gradient pulse is ramped up, held steady, and then ramped
down to zero, will necessarily be influenced by the applied
gradient. These transition samples may provide other interesting
information, but are not used in the consideration of a straight
measurement of the k-value coefficient; only those samples which
are recorded when there is no gradient currently active are used
for this.
A consistent number of samples at each k-value can be acquired, or
an alternative sequence may be employed where, as k-values
decrease, hence increasing in signal amplitude, fewer samples are
acquired. A pulse sequence designed for this type of acquisition is
illustrated in FIG. 5. Multiple samples of each k-value targeted in
the acquisition are acquired in rapid succession, with all
gradients off. These repeats provide the input for signal averaging
in low SNR signals. As with the pulse sequence, depicted in FIGS. 3
and 4, the underlying signal is minimally impacted by motion due to
the very short time window in which data is acquired for a given
k-value.
Samples within the portions of the sample window 344a-344g outlined
on FIG. 5 correspond to the number of samples acquired for a given
k-value 340a-340g each induced by an unwinding pulse 342a-342f of
the k-value selection gradient. N.sub.k, the number of samples
associated with a given k-value, can be selected based upon
expected SNR, tissue contrast, contrast to noise, pathology,
texture size, and/or texture bandwidth. For the example in FIG. 5
it can be seen that a decreasing number of samples are taken for
progressively smaller k-values (larger textural features). This is
because, as previously discussed, to first order signal amplitude
increases with decreasing k-value--energy density is generally
proportional to k.sup.-1. For this same reason, larger k-values are
acquired first in this scheme, when T2 effects are least, the
longer wavelength, higher signal strength, k-values being recorded
later in the acquisition.
Refocusing the echo, and/or a new TR can be used to build up a
library of k-space samples. Acquisition of multiple k-values within
one TR can be facilitated by application of multiple refocusing
gradients and/or RF pulses, to increase the time over which the
additional k-values can be sampled within a TR. These later echoes
would presumably be used to acquire the coefficients of the lower
k-values in the selected set, as their energy density in the
continuum of values is generally higher so the effect of T.sub.2
decay on overall signal will not affect them as severely as it
would the higher k-values. In this way a larger portion of the
required k-space filling can be accomplished over fewer TRs,
allowing more rapid data acquisition, minimizing the need for
repositioning the VOI.
FIG. 8 shows an extension of the basic sequence of the embodiments
disclosed herein, using spin-echo refocusing to extend the record
time for the TR. Application of a refocusing RF pulse 802 with an
associated gradient pulse 804 results in slice-selective
refocusing. After an appropriate settling time, a second sampling
window 806 is opened by the receive gate 808. Multiple k-value
selection gradient pulses 810 are applied to increment the selected
k-value and, after switching off each successive gradient pulse,
multiple samples of the selected k-value are acquired in the
sampling window. A second slice-selective refocusing RF pulse 812
with associated gradient pulse 814 again inverts the spins and,
after application of each in the multiplicity of k-value selection
gradient pulses 820, data is acquired in a third sampling window
816, opened by the receive gate 818. As shown in the drawing, an
increasing number of k-values may be sampled with each refocusing.
Refocusing can be repeated until the decrease in signal level from
T2 and other effects makes further signal acquisition ineffective.
Another method to extend the record time by exciting multiple
signal echoes, is to use one, or a series of, gradient recalled
echoes (GRE). GRE are different from the SE in that they cannot
refocus the effects of stationary inhomogeneities, so T2* effects
limit the number of repeats.
In addition to the tissue contrast available, the k-values
associated with particular pathology will be part of the
determination of the number of samples needed for signal averaging,
N.sub.k. In liver fibrosis, as an example, the wavelength of
pertinent textures is in the range of 400 microns, i.e. a k-value
of 2.5 cycles/mm. This is similar to the textural spacings seen in
fibrotic development in many other diseases, such as cardiac
fibrosis. The spacing of elements in trabecular bone varies a lot,
but the minimum spacing of interest is the width of trabecular
elements, which are approximately 80 microns, setting a maximum
k-value of 12.5 cycles/mm. In neuropathology, many of the textures
of interest are very fine, on the scale of 50 microns, equivalent
to a k-value of 20 cycles/mm.
Each pathology will dictate what exactly is needed as quantitative
data, i.e. what part of the continuum of k-values needs to be
monitored, and with what resolution and sensitivity. In some
pathologies, short (long) wavelength features increase at the
expense of long (short) wavelength features (e.g. liver fibrosis).
In other pathologies, an amplitude decrease and broadening of short
wavelength features indicates disease progression--e.g. degradation
of the ordered formation of cortical neuronal minicolumns
(approximately 80-micron spacing) with advancing dementia. In bone,
with increasing age, first the highest k-value features disappear
in the structural spectrum. Next the major structural peaks shift
slowly towards lower k-values with advancing osteoporosis, the pace
of this shift accelerating as an increasing percentage of
trabecular elements thin to the point that they break.
The signal level obtainable will depend on anatomy to some extent.
For instance, though the resolution needed is highest in brain, the
proximity of the cortex to the surface of the head ensures that use
of a surface coil will provide significant signal boost for
cortical structures. Lower resolution is required in liver, as the
structures of interest are on the order of several hundred, rather
than tens of microns. But, the organ is deeper (further from the
coil) reducing the measured signal. Using the in-table coil for
spine data acquisition yields modest signal level and good
stabilization. Also, bone is a high contrast target, so the SNR
requirement is not as stringent. For all these reasons, the exact
number of repeats needed for averaging depends on more than the
k-value range targeted.
FIG. 6 shows a simulation demonstrating that the ability provided
by the claimed method to acquire many repeats of a targeted k-value
within a single TR, or single excitation pulse, enables robust
signal averaging to boost SNR. Assuming a subject displacement rate
(which has in practice been measured clinically over the course of
several scans) of 30 .mu.m/sec, and a sampling rate=33.3 kHz
(.DELTA.Tsample=30 .mu.s), 90 repeat samples for averaging can be
taken rapidly enough that, even up to a k-value of 20 cycles/mm
(texture wavelength=50 .mu.m), the acquisition remains immune to
motion effects.
FIG. 7 shows that, for comparison, using the conventional approach
of acquisition of a spatially encoded echo, even assuming a
relatively fast gradient refocus sequence, which would provide a
sampling rate of about 67 Hz (.DELTA.Tsample=15 msec), subject
motion over the time needed for 90 repeats would severely degrade
the signal, and any ability to improve SNR by signal averaging. The
situation is actually worse due to the fact that to acquire 90
repeats using conventional spatially-encoded echoes would require
several TRs, making the acquisition time significantly longer, and
the signal degradation due to motion much more severe. With the
exception of the very lowest k-values, the potential SNR gain due
to multiple sample combination has been nullified by the effects of
motion.
By acquisition of a large enough selected range of k-values,
construction of a structural profile in one or more dimensions
becomes a possibility. As discussed above, refocusing echoes within
a single TR or excitation pulse, or multiple TRs/pulses, can be
used to build up a library of k-space samples. Phase coherence
might not be maintained between different k-values if they are
acquired in TRs separated temporally such that displacement has
occurred between them. If a primary interest is in the relative
strength of signals at particular k-values, this is not a problem.
If creation of a profile or an image from this library of values is
desired, the necessary post processing will have as input the high
SNR measure obtained within each TR using the embodiments disclosed
herein. These measures can then provide robust input for any
required reregistration between echoes or TRs towards constructing
a profile. As an example selection and measurement in a first TR of
a set of selected k-values may be accomplished with at least one
having a low k-value. In a subsequent TR, selection of the same set
of k-values will allow re-registration of the data between the two
TRs since even if significant motion has occurred the phase change
in the low k-value phase shift will be less than for higher k-value
textures and may be correlated between the two TRs. Basically, the
higher the k-value, the greater the phase shift due to subject
motion. Acquiring signal from successive encodes with a large
difference in k-value enables a better estimate of phase shift by
careful comparison of the apparent phase shift for each.
This is very similar to x-ray diffraction, wherein the
magnitude-only information (no phase) obtained presents the
challenge of determining a best estimate of the corresponding
structural profile based on this magnitude-only information.
Algorithms exist towards solving the problem, the chance of success
depending on the range of k-value coefficients obtained, the SNR of
each averaged coefficient, and the width of values contained in a
nominally single-valued acquisition of k-value. The chance of
success in this effort is greatly increased using the claimed
method due to its immunity to subject motion.
The ability to reconstruct a profile from k-value data depends
somewhat on the spectral broadness of each single-k-value
acquisition. While this is influenced by the VOI (Volume of
Interest) size and shape, it is also influenced by k-value and
pathology, as degradation of tissue often tends to lead to more
textural randomness within tissue.
Selection of the VOI--shape, dimensions, orientation, and
positioning within an organ/anatomy affects the data measured and
its interpretation. The VOI shape can be chosen to maximize
usefulness of the acquired data. Data can be acquired in different
directions, and at different textural wavelengths (k-values) within
a VOI enabling assessment of textural anisotropy. Texture can be
sampled in multiple VOIs, either interleaved within a single
TR/excitation pulse, or in successive TRs, towards assessment of
pathology variation across an organ. Standard interleaving
processes for the VOI may be used within a TR to provide additional
data by applying additional encoding pulses on vector combination
gradients and associated k-value selection gradient pulses for
k-values in the interleaved VOL As previously described, additional
excitation RF pulses with associated slice selection gradients may
be repeated within the same TR by exciting a volume of interest
with a gradient set in each repeat having at least a first gradient
with an alternative orientation from the first gradient pulse 308
applied initially in the TR, to define an additional VOI for
excitation in new tissue, that does not overlap any previous VOI in
the TR (fourth, fifth and sixth gradients in a first repeat and
succeeding incremental gradients in subsequent repeats). This
response can be mapped, or the several measures taken and averaged,
whatever is appropriate for the targeted pathology. This is similar
to the multi-positioning of tissue biopsy. However, in the case of
tissue biopsy, the number of repeats is limited due to the highly
invasive nature of the technique. The minimum number of structural
oscillations to be sampled at a specific k-value dictates a minimum
VOI dimension in the direction of sampling--the length required
varying inversely with targeted k-value.
To ensure adequate sampling of structure when targeting a range of
k-values, the VOI dimension in the sampled direction can be held
constant for all k-values in the targeted range, with the result
that the number of structural oscillations sampled will vary with
k-value. This is a simple solution, requiring the sampling
dimension be set by the lowest k-value (longest wavelength
structure). Using this approach, the sampling dimension of the VOI
is larger than required for the highest k-value in the range, thus
providing less localization within the tissue than would be
otherwise possible.
Alternatively, data at widely differing k-values can be acquired in
successive TRs, using changing VOIs tailored to the specific
k-value targeted. Or, the dimensions of the VOI can be selected
such that acquisition in different directions within the VOI will
be tailored to sampling in a specific textural frequency (k-value)
range.
Similarly, the VOI may be held constant and the vector combination
gradient for the encoding and k-selection pulses may be altered
from TR to TR for assessing feature size.
In some instances, it is desired to localize tightly in the spatial
domain, to broaden the localization in k-space. By defining a
non-cubic acquisition volume, it would be possible to acquire data
from differing k-values along the different (orthogonal or other)
directions within the VOI, within one TR. The elliptical
cross-section VOI 902 in FIG. 10 is one such possibility.
Acquisition along any radial direction, as well as along the axis
of the shape, would be possible within one TR.
Additionally, the flexibility of the embodiments disclosed herein
may be used to sample k-space in a linear or in a curved
trajectory. For example, texture could be sampled along radial
lines, or along an arc or a spiral, to extract information of
textural sizes along different spatial directions. These methods
can be used to determine the anisotropy of texture, or the
sensitivity to alignment in structures that are semi-crystalline,
such as cortical neuronal columns, or to more rapidly build up a
library of k-values within a targeted extent of tissue in an
organ.
During one TR (i.e., one 90 degree excitation) k-value encodes can
be applied in multiple directions by changing the applied vector
combination gradients for encoding and k-selection pulsing. The
exact form of the VOI and sampling direction can be used to yield
much textural information. For instance, the organization of
cortical neuron fiber bundles is semi-crystalline, as the bundles
in healthy tissue form in columns. Because of this, the measure of
textural spacing perpendicular to the bundles is very sensitive to
orientation. When the orientation is exactly normal to the columns,
a very sharp signal maximum is expected, the signal falling off
rapidly as the orientation varies on in either rotational direction
away from this maximum. One way to measure the spacing and
organizational integrity (a marker of pathology) would be to "rock"
the acquisition axis around this maximum looking for a resonance in
signal intensity. This approach of looking for "textural
resonances" by looking for signal maxima can be applied in any
tissue region. As pathology degrades the organizational integrity,
the sharpness of this peak will degrade and the signal maximum will
be reduced.
Similarly, the randomness of the spacing in certain textures can be
assessed by varying the length of tissue sampled in a specific, or
in multiple directions, with subsequent change in acquisition
length. The selected value for that length can be varied over
multiple TRs to test the sensitivity of the measured coefficient to
this parameter.
The VOI can be selectively excited by a number of methods, for
instance intersecting slice-selective refocusing, selective
excitation using phased-array transmit in combination with
appropriate gradients, adiabatic pulse excitation to scramble
signal from the tissue outside the region of interest, as examples.
Parameter selection for the various methods can be done with SNR
optimization in mind. For instance, the VOI generated by a slice
selective excitation and two additional mutually-orthogonal slice
selective refocusing pulses, as by VOI 904 in FIG. 9. Through
careful RF pulse design, the shape of the VOI can be designed so
that the edges are smooth and more approximate a windowing
function, as shown in FIG. 10. These windowing functions provide
the volume selection without adverse impact on the spatial
frequencies. Recall, in Fourier theory, each spectral line is
smeared by the convolution of a Fourier transform of the window
function. It is desirable to minimize this smearing of the
underlying spectrum, as it decreases the energy spectral density,
and adversely impacts SNR.
Importantly, as has been discussed previously, the VOI can be moved
from place to place within an organ or anatomy under study to
measure the variation of texture/pathology. This response can be
mapped, or the several measures taken and averaged, as appropriate
for the targeted pathology. This is similar to the
multi-positioning of tissue biopsy. However, in the case of tissue
biopsy, the number of repeats is limited due to the highly invasive
nature of the technique.
Different diseases and conditions affect tissue in different ways.
Generally, pathology advancement entails: 1) a loss of energy
density in specific regions of k-space, and/or 2) a shift in
textural energy density from one part of k-space to another, both
effects being accompanied by 3) changes in the width of existing
peaks in the continuum of textural k-values. Using trabecular
structure as an example--with decreasing bone health the average
separation of trabecular elements widens (texture shifts to lower
k-values) and becomes more amorphous (broader peaks in k-space),
while in parallel the structural elements thin (a shift to higher
k-values in a different part of the spectrum). Other tissues/organs
are affected by diseases that have their own individual signatures
in tissue texture.
Using the embodiments disclosed herein, k-space is probed to reveal
texture in such a way as to eliminate the loss of signal resolution
that results from subject motion blurring. Instead of measuring the
large continuum of k-values needed to create an image, the focus
here is on acquisition of a select few k-values per TR, with
sufficient repeats of each to yield high SNR. Each of the
individual acquisitions is centered on a single k-value. While the
spatial encode is, to first order, a single spatial frequency
sinusoidal encode, there are a number of factors which have the
effect of broadening the spatial frequency selectivity of the
k-value measurement. One significant factor affecting the
broadness, or bandwidth, of the k-value measurement is the length
of the sampled tissue region. A longer sampling length encompasses
more textural wavelengths along the sampled direction, which has
the effect of narrowing the bandwidth of the k-value measurement.
(This is the inverse relationship between extent of a measurement
in real and in k-space.) Hence, an aspect of the claimed method is
the ability to set the bandwidth of the k-value measurements by
appropriate selection of the sampling length determined by the VOI
dimensions or determined by the acquisition dimensions. Using this
method, the bandwidth of the measurement can be set according to
the desired k-space resolution appropriate to the tissue being
evaluated. (Need both high k-values for good texture resolution,
and high resolution in k-space for sensitive monitoring of
pathology-induced changes.) For highly ordered structures one could
choose a set of narrow bandwidth measurements distributed over the
expected range of texture wavelengths, whereas in a more randomly
ordered structure, such as the development of fibrotic texture in
liver disease, one could choose to use a single, or a few,
broadband k-value measurements to monitor development of the
fibrotic texture.
A measure of both the relative intensities of the various textural
k-values present in a tissue and the broadness of the peaks along
the continuum of textural k-values present within the texture under
study is needed. As such, data acquisition can be designed to probe
specific region(s) of k-space, with parameter selection that will
enable measurement of the relative width of peaks arising from the
underlying tissue, rather than that resulting from experiment
parameters. It is necessary to recognize the interaction of the two
components, and design experiments to yield the best measure of
pathology-induced tissue changes.
It is desirable to obtain a good measure of texture by acquiring
multiple measures of signal amplitude at specific k-values close in
time before motion blurs the data, taking repeat measurements in
minimal time to allow best inter-measure correlation for averaging.
An alternative to acquiring many repeat measures at one point in 3D
k-space, is to acquire data with a gradient on, such that the
k-value is changing continuously across the acquisition, the extent
in k-space being determined by the height of the gradient and its
pulse width. In addition to varying the magnitude of the k-vector,
its direction over the course of data acquisition can also be
varied. Combination of direction and magnitude changes across an
acquisition result in a curvilinear trajectory through k-space. If
this deviation is small enough that the k-values remain correlated
to some extent, they can be combined more effectively to increase
SNR than if they were simply averaged. Gradient on acquisition can
therefore be used to intentionally vary the direction and magnitude
of the k-vector, for the purpose of smoothing signal speckle--which
manifests as a time varying signal over the data acquisition,
resulting from interference of the individual spin signals' varying
phases and amplitudes. The selected variation in k-value direction
and magnitude across the acquisition is chosen to provide
sufficient combined measures to get an estimation of the
representative power within a neighborhood of k-space.
Varying the k-value to reduce speckle can be accomplished within a
single, or multiple, echoes. For a sphere in k-space, defined by
the magnitude of the k-value under study, the k-value can be varied
by keeping the magnitude of k-constant but sweeping the vector over
the surface of the sphere, or the same angular orientation may be
maintained, and the magnitude of k varied, or both can be varied
simultaneously
For the purpose of reducing speckle effects, these variations would
usually be small enough deviation from either the k-magnitude or
direction that there is a meaningful correlation between the
measurements for the particular tissue under investigation.
The major components of the spatial frequency will be the same in
all those measurements (they are correlated) unless the measured
tissue is a highly crystalline texture. But the normal diffraction
pattern for a micro-crystalline or amorphous structure has a lot of
speckle. Consequently, by sampling a number of points in the same
region of k-space they can be combined in various ways, selected to
provide optimal smoothing to reduce the speckle-pattern. A better
and more robust measure, from averaging out the fluctuations, is
the result.
A number of approaches to "dither" k-value to reduce speckle or to
tailor width in k-space may be employed. A first approach employs
constant k-magnitude plus sweeping through a range of angles by
keeping gradients on during acquisition and combining the measures
using correlative information to eliminate speckle. Alternatively,
the same direction in k-space may be maintained but the magnitude
varied by leaving gradient on during acquisition and combining the
measures using expected correlation. As yet another alternative,
both magnitude and direction may be varied simultaneously or over
an acquisition series, essentially performing the other two
alternatives simultaneously to both reduce noise and provide a
better assessment of the representative k magnitude in a structure
in a "small" region around a specific k-value, i.e., to reduce
speckle.)
For combining the measures at different k-magnitudes, for noise
reduction averaging, there is a phase shift from one radius
(magnitude) to the next from the gradient wind-up. Rephasing may be
accomplished before averaging.
Combining the different magnitude measures in an amorphous
structure is more well-known than combining different angled
measures. Now in addition to the scheme of reducing thermal noise
by rapid sampling the fluctuations due to speckle (which though
real signal confounds good assessment of the spatial frequency) may
be reduced.
A dynamic k-space acquisition is therefore employed. The
acquisition mode is dynamically chosen based upon the Signal to
Noise Ratio (SNR) of the signal at various k-space locations. The
gradient, applied during signal acquisition, post-acquisition
receive bandwidth, and estimation algorithms used are dynamically
adjusted based upon the expected SNR values in k-space to optimize
acquisition time and post-processed SNR. In regions of high SNR, a
single sample at a given k value may be a sufficient estimator.
This requires a relatively wide receive bandwidth to accommodate
the relatively rapid signal variations in the receive chain as k is
changed rapidly (due to the large gradient).
In regions of moderate-to-low SNR, the gradient magnitude is
decreased so that, subsequent samples, while not taken at identical
k values, are correlated, which in turn can be used to improve
estimates of the underlying signal values within that range of
k-values.
Correlation may be introduced in k-space due to selected windowing
in profile space. To enable combination of sequential samples from
the ADC so as to improve SNR, correlation among successive samples
will be increased by proper choice of windowing in profile space, a
shorter window driving a greater correlation distance across
sequential values in k-space and a longer window resulting in lower
sample to sample correlation. Inducing correlation of neighboring
points in k-space by windowing in profile-space is a mathematical
tool that can, in many cases, help to measure the underlying
texture in a low SNR environment. Basically, windowing blurs the
data so that the k-value power spectrum is smeared out through
k-space, so that sequential measures can be averaged/combined more
easily to increase SNR.
In a very high SNR environment as large a window as possible is
used because a measure of the actual textural power distribution
across a range of k-space is desired. The longer the sampled region
in real (profile) space the more accurate the measurement when
measuring amorphous textures. Reducing the sampled region by
windowing to induce correlation in k-space actually obscures the
specific desired measurement point.
However, while facilitating measurement, inducing correlation
through windowing does blur to a greater or lesser degree the
underlying relative power density profile in k-space arising from
the underlying texture, which is the target of the measurement. As
the sample-to-sample spacing (determined by the analog to digital
converter speed and gradient height) in k-space decreases, there
will be increased correlation, which can be used in
post-acquisition processing to form better estimates. Additionally,
the receive bandwidth in these regions can be decreased, which
further decreases the noise floor.
In regions of very low SNR, multiple acquisitions of the measured
signal level at a specific k value can be taken, with zero (and/or
non-zero) gradient during acquisition. The multiple acquisitions
can then be optimally combined to provide an estimate for specific
k values.
An example Hybrid pulse sequence is shown in FIG. 11. This
particular sequence is an example of a rapid acquisition with
refocused echoes (RARE) type sequence wherein three different
levels of gradient are used for acquisition as illustrated across
three separate echoes. The shown pulse sequence for selecting the
desired VOI and initial phase wrap for k is as described in FIG. 3
and is numbered consistently in FIG. 11. While this exemplary pulse
sequence for establishing the VOI is employed in the various
examples disclosed herein, the determination of VOI may be made by
any of numerous approaches including, as an example, time varying
RF pulses with commensurately time varying gradients applied.
Similarly, during or after the pulse sequence employed for
determining the VOI, the encoding gradient pulse may be applied for
selection of the initial k-value. The data recording starts with
acquiring values in regions where |k|>>0, given that the
signals are smallest there and should be acquired first. The second
echo samples values associated with |k|>0, but whose signal
levels are still relatively small and require combination of
multiple measures to provide robust SNR. The final echo samples
values associated with |k| in the neighborhood near |k|.about.0
where the corresponding signals are largest. Note that this is just
one example of how this hybrid approach, using both zero and
non-zero gradient in one acquisition, could be used. Different
amounts of k-value windup (as determined by the gradient height and
pulse duration) can be acquired in one echo rather than in multiple
echoes as will be described subsequently. Multiple combinations of
the differing k-value windup also can be acquired within one echo.
Additionally, while refocusing is disclosed in the drawings as
employing an RF pulse, gradient refocusing may also be
employed.
Details at expanded scale of the pulse sequence/signal acquisition
are shown in FIG. 12. In this sequence, the first echo from RF
pulse 328 with gradient pulse 332 uses the a pulse sequence similar
to that previously described with regard to FIG. 3 and acquisition
of multiple samples with gradient=0 and incrementing of k values
with k value selection gradient pulses 1100a, 1100b and 1100c. This
samples multiple values of a given location in k-space, which
values are then optimally combined. This is appropriate for regions
of k-space whose values are very small and therefore have very low
SNR. This typically occurs in regions where |k| is large.
The second echo from RF pulse 1102 with gradient pulse 1104 is
acquired with a small non-zero gradient 1106 acting as a time
dependent phase encode. A small gradient may be defined as: a
gradient that induces samples in k-space which will be sufficiently
closely spaced so that the samples are highly correlated. These
samples can then be post-processed by an estimator which takes
advantage of the high inter-sample correlation to improve the
resulting SNR. Quantitatively an exemplary "small" gradient might
be up to 20% of the magnitude of the encoding gradient pulse. As
seen in the figure samples of multiple values in a relatively small
neighborhood, .DELTA.k, in k-space are obtained. The spacing of
.DELTA.k can be chosen such that, due to the windowing of the VOI,
there is high correlation between neighboring samples. The
correlation is exploited in the estimation algorithm to generate an
optimal estimate of the signal levels across a neighborhood in
k-space. This is appropriate for regions of k-space which have low
SNR, but whose values, because of the correlation induced by the
windowing function, vary slowly across k-space in a small
neighborhood.
A third echo from RF pulse 1108 with gradient pulse 1110 is
acquired with a relatively larger time dependent phase encode
gradient 1112. The higher gradient employed herein creates
sequential measurements in k-space which have a lower degree of
correlation across the neighborhood of k-space under study. In this
case, there is lower inter-sample correlation available for SNR
improvement. A higher gradient may be employed for sampling k-space
locations whose values have a high SNR to begin with (such as would
be seen in lower textural frequency (low k-value) regions). As seen
in the figure samples relatively widely spaced across k-space, well
outside the inter-sample correlation imposed by the window
function, are generated over the entire pulse. This is appropriate
for rapid acquisition of values in k-space whose signal levels are
relatively high and enable high SNR recording. In this case, a
single sample at a given point in k-space provides a high enough
signal. However, in such higher SNR regions, the higher gradient
may be employed and selected bursts of data samples may be rapidly
recorded. Each of these bursts will have substantial inter-sample
correlation within the burst and may allow computation of results
similar to that described for the lower gradient acquisition
discussed above. This may be viewed as transitioning along the
K-space line with the higher gradient while sampling blocks of data
at closely spaced k values to maintain correlation.
Non-zero gradient acquisition allows sweeping across a curvilinear
path in k-space. By a judicious choice of time increment, .DELTA.t,
gradient magnitude, G, w(X), and the total number of samples
acquired, N, the neighborhood of "high" correlation can be adjusted
to be M<N. This in turn would allow estimation of a multiplicity
of distinct values within k-space by using a subset of M samples
for each output estimation. Textural data from within a tissue
region defined by the VOI can be acquired with the non-zero
gradient to enable determination of the local distribution of power
density of k-values within a neighborhood in k-space. The extent of
k-space sampled with a gradient pulse played out during acquisition
is determined by the gradient height and the gradient pulse width
(pulse duration). The spacing between signal samples in k-space is
determined by the gradient height and the sampling rate (limited by
the maximum speed of the analog to digital converter). The
correlation between sequential samples in k-space is determined
then by the spacing between samples, by subject motion, by the
window used to bracket the acquisition in physical space, and by
the underlying texture.
A useful method for selecting the acquisition parameters is with
reference to the degree of correlation needed within a set of
values to be combined. The wavelength of a repeating structure
(texture) is defined as the inverse of the k-value associated with
that texture, .lamda..sub.texture=1/.lamda..sub.texture. To be able
to combine a set of values [measurements] to yield improvement in
SNR, the underlying textural signals must not be shifted in phase
by a significant percentage of .lamda..sub.texture relative to each
other. In exemplary embodiments, the phase shift across the set of
samples to be combined should be no greater than 80% of 2.pi..
Resolution in MR imaging is limited by subject motion during image
acquisition. This limitation can be very severe with non-compliant
patients. In addition to patient motion/compliance, the resolution
achievable in MR imaging which is exemplary art comparable to the
present invention, depends on several factors, such as tissue
contrast, organ, coil type, proximity to coil. Robust imaging of
structures below about 5 mm in extent is problematic, and anything
below about 1 mm is outside the realm of routine clinical imaging.
This is a clear shortcoming as many tissue textures in the range of
about 5 mm down to 10 .mu.m develop and change in response to
pathology development, hence measurement of these textures can
provide much diagnostic information--these tissue changes are most
often the first harbinger of disease. It is this textural
wavelength range, from about 5 mm down to 10 .mu.m that is targeted
with the presently disclosed method.
To measure tissue texture, the range of wavelengths in real space
which can be resolved, i.e. the wavelengths of the textures
pertinent to the particular pathology, are in the range of several
mm down to microns. This is the range made inaccessible (blurred)
in imaging due to patient motion. As k is defined as 1/wavelength,
a range of k-values from about 0.2 mm.sup.-1 to 100 mm.sup.-1 is
employed in exemplary embodiments to define the textures of
interest. This brackets the region of k-space of interest, and
defines the gradient height and duration of the encoding gradient
pulse to induce phase wrap to create a spatial encode for the
specific k-value and orientation as well as for the non-zero
gradients applied for measurement of the neighborhood around the
initially selected k-value. The method of the embodiments herein
for sample acquisition and post processing may all be conducted in
k-space. The only localization in real space is the positioning of
the VOL Just enough of the neighborhood around a point in
real-space is sampled to measure texture--i.e. to determine the
power distribution within a neighborhood in k-space around the
selected point in real space.
The exact range needed varies with the targeted pathology. For
example:
Osteoporotic development in bone microarchitecture. As examples,
the variation in average trabecular spacing (TbSp) from healthy to
osteoporotic bone brackets a wavelength range of about 0.3 mm to 3
mm; the equivalent range of k-values is 0.34 mm-1 to 3.4 mm-1. With
fibrotic liver disease monitoring change in liver tissue texture
from the healthy collagen-highlighted vessel-to-vessel spacings to
the diseased state in which the lobule-to-lobule spacing becomes
the prominent tissue texture. Vessel-to-vessel range is 0.4 mm to
1.5 mm translating to k-values of 0.67 mm.sup.-1 to 2.5 mm.sup.-1
while lobule-to-lobule spacing of approximately 1 mm to 4 mm,
translating to k-values from 0.25 mm.sup.-1 to 1 mm.sup.-1.
Angiogenic vasculature development around a tumor site typically
changes from the healthy vessel texture spacing of around 100
.mu.m; k=10 mm.sup.-1. Due to its chaotic nature, the spacings in
angiogenic vasculature cover a broad range from about 10 .mu.m to 1
mm, or 1 mm.sup.-1 to 100 mm.sup.-1. Diagnostic assessment of
dementia-related changes to the cortical neuronal spacing involves
measuring high k-values, the healthy structure being about 100
.mu.m spacing or k=10 mm.sup.-1. Variations of about 10-20% of this
value, with increasing randomness in structure, mark the
disease.
Therefore, the acquisition parameters can be chosen such that (1)
the gradient height/duration generates a range of k-encodes
spanning the neighborhood of k-space over which it is desired to
inspect the power density present in the targeted tissue texture,
(2) the samples to be combined must occur close enough in time that
there is no significant blurring due to subject motion across the
acquisition time of a block of samples to be combined, and (3) the
tolerable amount of motion depends on the neighborhood of k-space
under investigation (i.e., the wavelength).
Acquisition of textural data from within a targeted VOI with the
non-zero gradient enables determination of the local variation of
power density of k-values within a neighborhood of the initial
k-value in k-space. The extent of k-space sampled at each gradient
pulse is determined by the gradient height and the pulse width.
Spacing between the samples in k-space is determined by the
gradient height and the sampling rate.
These parameters are selected (1) to allow acquisition of
sufficient data for combining toward significant SNR improvement,
before subject motion can blur the data significantly relative to
the texture to be measured, (2) to ensure sufficient correlation
across the blocks of k-values from the acquisition to be combined
to maintain a SNR.gtoreq.0.5 dB, and (3) to set the extent of
k-space over which the power density of k-values present in the
texture is desired.
Blocks of sequential signal samples to be recombined for SNR
improvement can be non-overlapping, or overlapping by a selected
number of points, or a sliding block used so as to combine, for
example, measures 1-4, 2-5, 3-6 and so on as will be described
subsequently. Additionally, the number of samples in each block may
be varied from block to block across the extent in k-space of the
acquisition, this variation in number of samples to be combined
being determined by the requirement for sufficient correlation to
maintain SNR sufficient to provide a robust measurement. The
approximate noise level can be determined independently by several
methods well known to the industry including measuring noise in the
absence of signal input.
Acquiring data with different magnitude gradients within one echo,
TR, or scan may be accomplished with the successive gradient
heights being selected to enable best SNR of the combined signal at
the various targeted regions of k-space. To enable combination of
sequential samples from the ADC to improve SNR, correlation among
successive samples can be increased by proper choice of windowing
in profile space, a shorter window driving a greater correlation
distance across sequential values in k-space and a longer window
resulting in lower sample to sample correlation. The window width
selected is defined by both the desire for correlation across many
samples in k-space, which dictates a shorter window, and the need
to sample a sufficient extent of texture in real space to provide
robust measure, especially when measuring highly amorphous
textures.
Post-acquisition combination of the signals acquired in k-space in
blocks, the number of samples to be combined determined by the
requirement that the correlation between the individual signals to
be combined be sufficient to achieve a SNR.gtoreq.0 dB (the level
of correlation is determined by subject motion, gradient height,
sampling rate, window shape, and the underlying texture.)
Use of non-zero gradient acquisition may be employed to
intentionally vary the direction and magnitude of the k-vector over
a range during data acquisition, for the purpose of smoothing
signal speckle--which will manifest as a time varying signal during
the data acquisition--that results from interference of the varying
phases and amplitudes of the individual spin signals. The selected
variation in k-value direction and magnitude during data
acquisition is chosen to provide sufficient combined measures to
get a an estimation of the representative power within a
neighborhood of k-space, with a SNR of 0 dB, where the neighborhood
is within 20% of the 3D orientation and magnitude of the centroid
of the neighborhood.
Correction for change in k across a set neighborhood created by
application of a non-zero gradient may be accomplished by employing
proscribed k encodes for a specific set of k measurement.
Additionally, correlation within a set of k measurements acquired
within a time period and from a selected VOI can be induced by
selecting the time period such that the biological motion is
sufficiently small that the phase shift in the data induced by
patient motion is less than 50% of the wavelength corresponding to
the targeted textural k-value range. Alternatively, a windowing
function may be selected such that there is sufficient correlation
between individual measurements and the set estimate that a desired
SNR can be achieved.
Details of the very-low SNR acquisition mode at even further
expanded scale are shown in FIG. 13. In this portion of the
sequence, the k-value is constant at an initial value 1114a, a
second value 1114b induced by k value selection gradient pulse
1100a, a third value 1114c induced by k value selection gradient
pulse 1100b and a fourth value 1114d induced by k value selection
gradient pulse 1100c in the region 1116 where the sample gate is
open thereby producing samples 1118. This is the previously
described pulse sequence where multiple repeats of signal at the
same k value are rapidly sampled, all of which are then combined
into one estimate.
Details of the low SNR acquisition at the further expanded scale
are shown in FIG. 14. In this portion of the sequence, notice that
the k-values do change as shown by trace segment 1120, albeit
slowly, due to the non-zero time-dependent phase-encode gradient
1106 present during the recording of the region 1122 when the
sample gate is open. However, the range of samples 1124 across
k-space is a relatively compact neighborhood where the values are
highly correlated due to the windowing function.
Details of the high SNR acquisition at the further expanded scale
are shown in FIG. 15. In this portion of the sequence, the k-values
again change as shown by trace segment 1126, due to the non-zero
time-dependent phase-encode gradient 1112 present during the
opening of the sample gate in region 1128. The range of samples
1130 across K-space is still a relatively compact neighborhood, but
outside the inter-sample correlation imposed by the window
function.
The low SNR and high SNR acquisition modes with non-zero gradient
are distinct from a standard frequency-encoded MRI sequence as the
applied gradient is not used to establish a position, i.e.
frequency encoding, but as a time dependent phase encode to rapidly
acquire a number of individual samples across a relatively broader
neighborhood of k-space.
As previously asserted, gradient acquisition can be acquired in one
echo rather than in multiple echoes as seen FIG. 16. Again the
illustrated pulse sequence for selecting the desired VOI and
initial phase wrap for k is as described in FIG. 3 and is numbered
consistently in FIG. 16.
As seen in FIG. 16 and at larger scale in FIG. 17, the k-value is
constant at an initial value 1614a, a second value 1614b induced by
k value selection gradient pulse 1600a and a third value 1614c
induced by k value selection gradient pulse 1600b. Note that the k
values are decremented as opposed to incremented in the example of
FIG. 12. This is again the previously described pulse sequence
where multiple repeats of signal at the same K value are rapidly
sampled 1622a, 1622b and 1622c, all of which are then combined into
one estimate.
In a second portion of the sequence, within the same echo, the
k-values do change as shown by trace segment 1620, albeit slowly,
due to the non-zero time-dependent phase-encode gradient 1606
present during sampling. However, the range of samples 1624 across
k-space is a relatively compact neighborhood where the values are
highly correlated.
In a third portion of the sequence, again still within the same
echo, high SNR acquisition is conducted. The k-values again change
as shown by trace segment 1626, due to the non-zero time-dependent
phase-encode gradient 1608 present during the opening of the sample
gate. The range of 1628 across k-space is still a relatively
compact neighborhood but outside the inter-sample correlation
imposed by the window function.
As seen in FIG. 18 (and in larger scale in FIG. 19), where the
illustrated pulse sequence for selecting the desired VOI and
initial phase wrap for k is as described in FIG. 3 and is numbered
consistently in FIG. 18, a low non-zero magnitude gradient 1802
acting as a time dependent phase encode is applied and data samples
1804 are taken from an initial k-value 1806 for slowly time varying
k-values, seen in trace segment 1808, having high correlation as
previously described. The initial phase wrap may be selected to
provide an initial k-value with a magnitude corresponding to a low
SNR region.
Similarly, as seen in FIG. 20 (and in larger scale in FIG. 21), a
pulse sequence for selecting the desired VOI and initial phase wrap
to set the k-value region is illustrated and is as described in
FIG. 3 and is numbered consistently in FIG. 20. A higher non-zero
gradient 2002 acting as a time dependent phase encode is applied
and data samples 2004 are taken from an initial k-value 2006 for
more rapidly time varying k-values, seen in trace segment 2008. The
initial phase wrap may be selected to provide an initial k-value
with a magnitude corresponding to a higher SNR region. The encoding
gradient 326 may be employed to wind up to the lowest or highest
k-value in a targeted texture and the non-zero magnitude gradient
pulse is imposed in the necessary direction (increasing or
decreasing k) to reach the other limit in k-space to define the
texture.
The acquired samples may be outside the inter-sample correlation
imposed by the window function. However, signal levels for the
k-values are relatively large and have high SNR. Additionally as
previously described, rapid acquisition of samples in subsets
2010a, 2010b, 2010c and 2010d as exemplary, may be accomplished in
a manner that the samples within the subset may remain sufficiently
correlated and may provide desired data in structures having
predetermined or anticipated texture. One can combine however many
sequential values are correlated enough to yield an improvement in
SNR via the combination (averaging being one simple form of
combining). Then, the set of combined data points is used to
characterize the power distribution across the entire acquisition,
to get a better measure of the underlying texture within the
VOI.
As previously discussed, rephrasing separate low and high k values
based on low phase change in a second 90-180-180 excitation (TR).
SNR is maximized with gradient ON acquisition by smart combination
of successive k-value samples through reregistration of successive
acquired signals. Data is acquired across a range of k-space for
which the wavelengths are sufficiently long that subject motion can
be easily corrected for by reregistration--i.e. the phase shift
induced in the measure in this k range is much less than the
textural wavelength. The low k-value signal is sampled in alternate
refocusing sequences, or sequential excitations (TR), with the
acquisition of the signal from the higher k-value range of
interest. TE long wavelength measure is used to determine the
motion-induced phase shift across the measurements. That phase
shift is then applied to the higher k-data prior to
reregistration.
A number of correlations are implied by spatial windowing.
If g(x) corresponds to a 1D (real-valued) signal, the corresponding
function in K-space is given by the Fourier transform as:
G(2.pi.k)=.intg..sub.-.infin..sup..infin.(x)e.sup.-j2.pi..times.kdx
(1) Which is frequently expressed as a Fourier pair as
g(x).revreaction.G(2.pi.k) (2)
Windowing is the process of limiting the extent of g(x) to a finite
region of compact support, but doing it in such a way to minimize
spectral artefacts due to discontinuities (artificially) introduced
by the truncation.
Despite the specific shape used of the window function, there is an
inverse relationship between the width of the window, and its
spectrum. This is due to the Fourier relationship
.function..alpha..times..times..revreaction..alpha..times..function..time-
s..pi..times..times..alpha. ##EQU00004##
Multiplying two functions has the effect of convolving their
respective spectra, i.e.
f(x):=g(x)h(x).revreaction.F(2.pi.k)=G(2.pi.k)*H(2.pi.k) (4)
The convolution can be thought of as a linear filtering of the
spectrum as though the spectrum was the input signal
The term
.function..times..pi..times..times..alpha. ##EQU00005## acts like a
low-pass filter to the G(2.pi.k) spectrum, which tends to smooth
out the signal: the larger the value of .alpha., the narrower the
low-pass filter. This creates a significant correlation between
adjacent values of F(2.pi.k).
Estimators which observe noisy samples of a filtered input are well
studied and can be applied to generate optimal estimates; Weiner
filters, Kalman filters, etc.
Dynamic acquisition modes may be employed wherein:
X corresponds to a 3D vector in image space,
g(X) corresponds to the value of the image at a given 3D spatial
location,
K corresponds to the 3D vector,
G(K) corresponds to the value in k-space of the image g.
For initial simplicity, the time-dependency of this signal is
ignored which in turn depends upon T1, T2, T2*, as well as signal
contribution due to differing isochromats (different chemical
species within the Volume) etc. In the sequel the effect of these
is taken into account
Basic Principles relied upon are:
Generally, SNR of G(K) is highest at |k|=0, then decreases with
increasing |k|
The rate at which SNR decreases is typically expressed as SNR
.varies.|k|.sup.-.alpha. where .alpha. is in the range of 1-3.
The sampling rate, combined with the magnitude of the gradient will
set the sample spacing (.DELTA.k) density in k-space for a given
VOI.
As the gradient magnitude is decreased, the sample density
increases (i.e. .DELTA.k decreases).
Depending upon the size of the windowing in image space, there is a
corresponding correlation implied.
For a generalized case the simplified MRI relationship between
spatial coordinates and K-space given by
.function..intg..intg..intg..times..function..times..times..times..times.-
.times..pi..times..times..times. ##EQU00006## Where r represents
the real valued 3-Dimensional spatial coordinates with units of
meters (m). I(r) represents the image which is a non-negative Real
function of spatial coordinates r. k represents the real valued
3-Dimensional k-space coordinates with units in cycles/meter
(m.sup.-1) S(k) represents the Fourier Transform of I(r) and is
generally a complex-valued function of k And the integral is over
the entire 3-Dimensional spatial plane.
In words, S(k) represents the corresponding value in 3-dimensional
k-space of the image function I(r).
The k-space coordinates, in turn, are a function of time and have
the general form
.times..times..times..times..intg..infin..times..times..times..tau..times-
..times..times..tau. ##EQU00007## Where is the proton gyromagnetic
ratio with value 42.576 MHz/T g(t) is a real-valued 3-Dimensional
function of time representing the gradient strength with units in
T/m. This function, is a design input as part of the pulse sequence
whose purpose is to manipulate the proton spins in some desired
way.
The integral in equation (7) indicates that the value of k(t) for a
given value of t, is computed as the integral of all previous
history of the gradient function. While technically correct, it is
often more convenient to express this as
.times..times..times..times..intg..times..function..tau..times..times..ti-
mes..tau..times..times. ##EQU00008##
Where now t.sub.0 represents a convenient starting time, k(t.sub.0)
is the corresponding k-value at t.sub.0, and the lower limit of the
integral starts at t.sub.0.
Making the dependence on time more explicit, equation (6) can be
expressed as
.times..times..intg..intg..intg..times..function..times..times..times..ti-
mes..times..pi..times..times..function..times..times..times..times..gtoreq-
. ##EQU00009## S(t) represents the complex-valued baseband signal
one might obtain during an MRI echo experiment which is played in
conjunction with a gradient sequence encoded in g(t).
Without loss of generality, k, g and r can be decomposed into
Cartesian components as k=[k.sub.xk.sub.yk.sub.z].sup.T
g=[g.sub.xg.sub.yg.sub.z].sup.T r=[r.sub.xr.sub.yr.sub.z].sup.T
(10) And express 9 as
.times..times..intg..infin..infin..times..intg..infin..infin..times..intg-
..infin..infin..times..function..times..times..times..times..times..pi..fu-
nction..function..times..function..times..function..times..times..times..t-
imes..times..times..gtoreq. ##EQU00010##
In general k(t) represents a curvilinear path within K-space as a
function of time.
Initially, to facilitate explaining the initial concept, evaluation
is confined along a single dimension by assuming k(t)=[k.sub.x(t) 0
0].sup.T. Equation (11) then simplifies to
.times..times..intg..infin..infin..times..rho..function..times..times..ti-
mes..times..times..pi..times..times..function..times..times..times..times.-
.gtoreq. ##EQU00011## Where
.rho..function..intg..infin..infin..times..intg..infin..infin..times..fun-
ction..times..times. ##EQU00012## And equation (8) reduces to
.function..times..intg..times..function..tau..times..times..times..tau..f-
unction. ##EQU00013## Define
.times..times..times..times..rho..times..times..times..intg..infin..infin-
..times..rho..function..times..times..times..times..times..pi..times..time-
s..times. ##EQU00014## Which is occasionally expressed as
R(k).revreaction..rho.(x) (16) To concisely indicate that R(k) and
.rho.(x) are Fourier Transform pairs. By comparing (12) to (15), it
can be seen that S(t) is just a time dependent progression across
various Fourier coefficients represented by S(t)=R(k(t)) (17) Where
the mapping between the time-value t and the corresponding K-space
coordinate is given by equation (14).
To generally model the receive signal In an actual MRI machine, a
combination of the desired signal and noise received by the
antenna. That signal is then filtered, amplified, down-converted,
sampled, and quantized.
The specific details are machine-dependent, but a simple model can
be developed to represent the output of the machine as follows:
Let Y(t) represent a combination of the signal of interest, and a
noise signal as Y(t)=S(t)+W(t) (18) Where S(t) is given in equation
(17) and W(t) is a complex-valued zero-mean, Additive White
Gaussian Noise Process with variance .sigma..sub.w.sup.2, i.e.
E{W(t)}=0 and
E{W(t)W*(t+.tau.)}=.sigma..sub.w.sup.2.delta.(.tau.)
The received signal Y(t) is then uniformly sampled
Y.sub.n=Y(t)|.sub.t=n.DELTA.t=R(k(t))|t=n.DELTA.t+W(t)|.sup.t=n.DELTA.t
(19) Which can be expressed more simply as
Y.sub.n=R(k.sub.n)+W.sub.n (20) Where the sequence k.sub.n is given
by
.times..times..times..times..times..times..intg..times..times..DELTA..tim-
es..times..times..DELTA..times..times..times..times..function..tau..times.-
.times..times..times..tau. ##EQU00015## Define
.DELTA..times..times..times..intg..times..times..DELTA..times..times..tim-
es..DELTA..times..times..times..times..times..tau..times..times..times..ti-
mes..tau. ##EQU00016##
Then Error! Reference source not found. (21) can be simply
expressed as k.sub.0=k(t)|.sub.t=0
k.sub.n+1=k.sub.n+.DELTA.k.sub.n+1 (23)
In words, then, the sequence k.sub.n is defined by a sequence of
increments which is determined by the integral between samples of
the gradient function.
Equations (20), (22) and (23) may be employed to describe the
signals under different gradient conditions disclosed herein.
Collecting samples of an echo which has been "pre-phased" through
some gradient activity before-hand, but now the gradient is no
longer held to zero as described above with respect to FIGS. 12, 14
and 15 can be analyzed as follows.
The signal is then given by equation (20) as
Y.sub.n=R(k.sub.n)+W.sub.n (24) And k.sub.n is given by equation
(21) as
.times..times..times..times..times..times..times..intg..times..times..DEL-
TA..times..times..times..DELTA..times..times..times..function..tau..times.-
.times..times..times..tau. ##EQU00017##
Since, measurement is occurring in a non-zero gradient regime, the
integral term is no longer zero, which implies that the sequence
k.sub.n is no longer constant, and in turn the sequence R(k.sub.n)
is no longer constant.
Since no assumptions have been made on the underlying structure of
I(r), it cannot be implied that there is any particular structure
or relationship amongst the values of R(k.sub.n). This puts us at a
distinct disadvantage when wanting to estimate useful signals in a
very low SNR environment.
A structure may be imposed on the values of R(k.sub.n) by applying
a multiplicative window function in the image domain. This is
accomplished by leveraging two Fourier Transform identities:
Multiplication in one domain corresponds to convolution in the
reciprocal domain.
Define the following Fourier Pairs: v(x).revreaction.N(k)
.rho.(x).revreaction.R(k) .zeta.(x).revreaction.Z(k) (26) Then, the
product in one domain corresponds to convolution in the reciprocal
domain: .nu.(x)=.rho.(x).zeta.(x).revreaction.N(k)=R(k)*Z(k)
(27)
Scaling in one domain corresponds to an inverse scaling in the
reciprocal domain. If .zeta.(x).revreaction.Z(k) then
.zeta..function..revreaction..function. ##EQU00018##
Windowing functions are typically used to limit the image space to
a finite, compact region of interest, while at the same time,
minimizing the adverse consequences on the corresponding image
spectrum due to the window itself. Those skilled in the art will
appreciate there are a wide variety of window functions which have
been developed, each of which have their own particular set of
characteristics.
For sake of illustration, consider the most basic window
function:
.times..times..PI..times..times.>< ##EQU00019## The
corresponding Fourier transform is given by
.times..PI..times..times..intg..infin..infin..times..PI..function..times.-
.times..times..times..times..pi..times..times..times..times..times..pi..ti-
mes..times..pi..times..times..times..times. ##EQU00020## which is
frequently expressed as the Fourier pair
.PI.(t).revreaction.sinc(f) (31) Using equation (28) a slightly
generalized version and its Fourier pair is
.PI..function..revreaction..times..times. ##EQU00021## Using
equation Error! Reference source not found. (27), the windowed
profile and
Fourier pair is
.function..PI..function..times..rho..function..revreaction..function..tim-
es..times..times..times. ##EQU00022## Using equation (24) as a
reference, the sampled MRI signal can be expressed as
Y.sub.n=N(k.sub.n)+W.sub.n (3) (34) Which, using (33), can be
expanded as
.intg..infin..infin..times..times..times..times..function..times.
##EQU00023## Where the convolution integral has been specifically
expanded.
The value of the convolution integral taken at k.sub.n is no longer
a function of) just one point of R(k.sub.n). For each point k.sub.n
the convolution integral computes a weighted sum of the values of
R(k) centered around k.sub.n The extent of the neighborhood in
k-space is inversely proportional to the parameter X: Smaller
values of X increase the width of the neighborhood in k-space.
For the embodiments herein the extent of the domain of values of
interest correspond to the collection of k-space values k.sub.0,
k.sub.1, k.sub.2, L k.sub.N-1. Define
.times..times..times..times. ##EQU00024## Which in turn are
functions of the time interval .DELTA.t and the function
g(.tau.).
For example, making a simplifying assumption that g(.tau.)=G where
G is a positive constant, then k.sub.n is just a uniform sampling
across a portion of k-space, and is given by
k.sub.n=k.sub.0+nG.DELTA.t (37) Then k.sub.min and k.sub.max is
given by k.sub.min=k.sub.0 k.sub.max=k.sub.0+(N-1)G.DELTA.t
(38)
While a simple sampling of k-space may be chosen, it is not
specifically required. Indeed there could be applications where
non-uniform and/or even non-monotonic sampling strategies could be
useful.
Ideally, the parameter X (and the window function) are chosen so
that the resulting weighted sum across the neighborhood of k.sub.n
is "wide enough" so that N(k.sub.n).apprxeq.C where C is a
complex-valued constant, but not so wide so as to lose significant
spectral resolution
For purposes of the disclosed embodiments herein a "small" non-zero
gradient may be determined based on selection of desired windowing.
From equation Error! Reference source not found. (10)
.function..times..rho..function..times..intg..infin..infin..times..rho..f-
unction..times..times..times..times..times..pi..times..times..times.
##EQU00025##
Assume that the nominal center point of the profile has shifted to
be centered around a point x.sub.0. This results in
.function..intg..infin..infin..times..rho..function..times..times..times.-
.times..times..pi..times..times..times..times..times..times..times..pi..ti-
mes..times..times..function. ##EQU00026## Which indicates that each
point in k-space is rotated in complex space proportional to the
offset x.sub.0.
It can be assumed that the gradient is a positive constant, then,
by equation (39) k.sub.n=k.sub.0+nG.DELTA.t (43) Substituting in
Error! Reference source not found. (42) produces
R.sub.x.sub.0(k.sub.n)=e.sup.-j.theta..sup.0e.sup.-jn.DELTA..theta.R(k.su-
b.n) (44) Where the initial phase offset .theta..sub.0 and the
phase increment .DELTA..theta. is given by
.theta..sub.0:=-2.pi.k.sub.0x.sub.0
.DELTA..theta.:-2.pi.G.DELTA.tx.sub.0 (45)
In the event that, due to the application of a properly specified
windowing function, R(k.sub.n).apprxeq.C a complex constant within
the neighborhood, the post-acquisition estimator would first
multiply an offsetting phase increment e.sup.jn.DELTA..theta. to
each acquired sample of R.sub.x.sub.0(k.sub.n) before combining and
generating the final estimate.
An estimate of .DELTA..theta. can be obtained from a sequence of
k-space samples taken of the windowed profile over lower k-values
(where the SNR is higher).
Correlation may be induced by windowing as one parameter as
discussed previously. Multiplication of the profile .rho.(x) by a
real-valued window function .zeta.(x) corresponds to convolution in
k-space by the Fourier relation
v(x)=.rho.(x).zeta.(x).revreaction.N(k)=R(k)*Z(k) (46)
Z(k) is treated as an impulse response of a linear filter which is
applied to the complex-valued signal R(k) in k-space to produce a
complex-valued output signal N(k).
The autocorrelation function of the output signal
R.sub.NN(.kappa..sub.1,.kappa..sub.2) can be expressed as a
function the autocorrelation of the input signal
R.sub.RR(.kappa..sub.1,.kappa..sub.2) and the impulse response Z(k)
as
.function..kappa..kappa..intg..infin..infin..times..intg..infin..infin..t-
imes..function..kappa..alpha..kappa..beta..times..function..alpha..times..-
function..beta..times..times..times..alpha..times..times..times..times..be-
ta. ##EQU00027##
Equation (47) is inconvenient because the autocorrelation function
of the underlying signal R.sub.RR(.kappa..sub.1,.kappa..sub.2) is
not usually known. A simplifying assumption is made that R(k) is a
white-noise, wide-sense stationary process, and express the
autocorrelation as
R.sub.RR(.kappa..sub.1,.kappa..sub.2)=.sigma..sub.R.sup.2.delta.(.kappa..-
sub.1-.kappa..sub.2) (48) With this assumption, (47) reduces to
R.sub.NN(.kappa..sub.1,.kappa..sub.2)=.sigma..sub.R.sup.2R.sub.ZZ(.kappa.-
.sub.1-.kappa..sub.2) (48) Where R.sub.ZZ(.kappa.) is the
autocorrelation function of the impulse response Z(k) and is given
by
.function..kappa..intg..infin..infin..times..function..times..function..k-
appa..times..times..times. ##EQU00028##
The mapping of k vs time is mapped as follows.
k.sub.n=k.sub.0+nG.DELTA.t (51) The normalized correlation
.eta..function..times..times..DELTA..times..times..function..times..times-
..DELTA..times..times..function..function..times..times..DELTA..times..tim-
es..function. ##EQU00029## measures the degree to which the
underlying sample points are correlated. In low SNR regimes, a high
correlation is desired across all of the samples and therefore
establish a lower bound:
.eta..ltoreq..function..times..times..DELTA..times..times..function.
##EQU00030##
Equations Error! Reference source not found. (50) and Error!
Reference source not found. (53) provide the defining relationship
between the window function impulse response Z(k), the gradient
strength G, the sample interval .DELTA.t, the number of samples N,
and the correlation lower bound .eta..sub.min.
For example, assume that the window function is defined to be
.zeta..function..PI..function. ##EQU00031## Where .PI.(x) is a
standard so-called rectangular function defined below, and X is a
constant.
.PI..function.>< ##EQU00032##
The impulse function Z(k) is given by the Fourier transform
.function..function..pi..times..times..pi..times..times..times..times.
##EQU00033##
The corresponding normalized correlation function .eta.(.kappa.) is
given by .eta.(.kappa.)=sinc(X.kappa.) (57)
Restricting the correlation to be lower bounded by
.eta..sub.min=0.95 then, by (53) the condition arises that
.eta..sub.min.ltoreq.sinc(XNG.DELTA.t) (58) This can be
approximated using the first two terms of a Taylor series as
.times..times..theta..theta..apprxeq..theta. ##EQU00034## Which can
be inverted and applied to (58) to produce
.DELTA..times..times..ltoreq..times..eta..pi..times..times.
##EQU00035## Which now explicitly expresses an upper bound on the
product of the gradient strength G, the sample interval .DELTA.t,
and the number of samples N.
Typically the sample interval .DELTA.t, and the number of samples N
are determined by other considerations. Taking these as given, the
maximum gradient level is then given by
.ltoreq..times..eta..pi..times..times..DELTA..times..times.
##EQU00036##
For a non-zero gradient data acquisition in this case, as long as
the gradient G is below the calculated upper bound, the samples
acquired will have the defined correlation level. This condition as
defined for purposes herein as a "small gradient" level.
Sampling past this limitation will result in lower sample
correlation and therefore have less of a potential post acquisition
SNR gain. A "higher" gradient may be defined as operating in this
condition. Gradient determination is affected by a number of
parameters including (1) choice of the window function (e.g.
rectangular, Tukey, Hamming, etc.) which influences the shape (and
to a certain extent, the width) of the "main lobe" in the impulse
response, (2) choice of window extent (the larger the extent in the
profile domain, the narrower the "main lobe" in the impulse
response), (3) the impulse response which may create an
autocorrelation function, (4) the desired level of correlation
which determines the effective width in k-space, within which the
samples must be contained, and (5) sampling rate*Number of
samples*gradient size which determines the actual sampling
neighborhood size (note, as long as this number is bounded by the
number contained in element (4)) the gradient remains in the "lower
gradient level" regime.
An exemplary embodiment maintains a constant ratio of textural
wavelength to length of VOI acquisition axis. As the targeted
k-value varies, the length of the VOI acquisition axis is varied
such that the ratio of the corresponding textural wavelength to the
acquisition length remains constant. The aim here is to keep the
number of textural "cells" sampled constant. In this way, the
differential broadening observed at specific points in k-space,
.DELTA.k, is expected to arise from sources other than sampled
length in real space, such as the finite width of the RF pulse or
the edges of the gradient pulse.
MR-based diagnostic techniques may be combined. Certain MR-based
techniques designed to look at very fine tissue structure provide
data that may be difficult to interpret in certain pathologies, as
they provide only an indirect measure of the underlying structures.
Diffusion weighted imaging and Magnetic Resonance Elastography
(MRE) are two such techniques. The method of this provisional
filing is a direct measure and hence would provide, in many cases,
a better measure of fine texture, and in some cases provides
complementary data to increase diagnostic capability. Combining
acquisition techniques can provide more robust measure of texture,
and hence of pathology.
The embodiments disclosed may be used in combination with Magnetic
Resonance Elastography (MRE). Currently, the main application of
MRE is as a diagnostic for liver disease to determine therapy
response, progression, need for biopsy, etc. Though the targeted
pathology is fibrotic development, the technique measures this
indirectly, through measurement of tissue stiffness. In many cases,
it is difficult to distinguish fibrotic development from other
stiffness-inducing conditions such as portal hypertension and
inflammation. Further, hepatic iron overload, which often results
from a compromised liver, will lead to low signal, hence inadequate
visualization of the induced mechanical waves.
The embodiments disclosed can provide direct measure of fibrotic
development in the liver and, as such, would provide additional
data on disease progression or response to therapy in the case of
the various triggers of fibrotic liver disease. It provides a local
measure within the targeted anatomy for calibration of other,
indirect measures, such as MRE, DTI, DWI, etc.
The embodiments disclosed may be used in combination with, or
replacement for, diffusion weighted imaging in tumors. The ability
to detect the edge of tumors with high accuracy would facilitate
accurate surgical removal. Using the embodiments disclosed, data
can be acquired in VOIs along a selected direction across a tumor
region, looking for the edge of the region of angiogenic
vasculature.
The ability to measure inside of tumors to gauge therapy response
would help in targeting intervention. As an example of the latter,
immunotherapy treatment of melanoma tumors induces swelling of the
tumor due to T-cell infiltration which, on a structural MR scan,
looks similar to malignant tumor growth. Hence, it is difficult to
decide whether to continue the therapy. The ability to look at the
state of the vasculature within and surrounding the tumor would
enable discernment of whether the growth is cancerous or is due to
immune system response. The embodiments disclosed would also
provide local calibration of the currently used DTI measures, which
are often difficult to interpret.
The embodiments disclosed may be used as a bone degradation measure
in oncology. It is well known that radiation and/or chemotherapy
often compromise bone health. A measure of changes to bone
resulting from cancer therapy would help in tailoring therapy and
to determine if there is need for intervention to protect bone
health.
Currently, as a follow-on to surgery and treatment for breast
cancer, patients are routinely put in the MR scanner to image the
breast tissue. The sternum is within the field of view for such
exams, enabling easy application of a short add-on sequence of this
method to measure changes to trabecular bone and thus obtain a
measure of bone health.
As further examples of potential use of the embodiments disclosed
in oncology, the embodiments disclosed may be used to measure and
quantify hyperplasiac development of mammary duct growth in
response to tumor formation and development or to measure and
quantify angiogenic growth of vasculature surrounding tumors to
stage development, type, and response to therapy. Ongoing treatment
after breast surgery often involves reducing estrogen levels,
further compromising bone health and, as such, referral for MR
scans for bone monitoring is common; use of the method disclosed
herein would enable robust and detailed evaluation of bone health
by direct measurement of the trabecular bone structure.
The disclosed embodiments are also complementary with Big Data and
machine learning schemes. The method disclosed complements the
trend towards use of comparison among large aggregates of medical
data to learn more about disease, increase predictive power for
individual patients and for specific diseases, and note trends
across various populations. Benefits of using the method of this
filing in conjunction with Big data/machine learning include:
Output measurements from application of the embodiments disclosed
can be compared over a population of unknown pathology, for
example, the variation in the power spectrum across targeted
k-values, could be compared to the occurrence of femur fracture in
the same population; the textural power distribution in cortical
neuron bundles can be measured and correlated with performance on
Alzheimer's mini-mental state exams, MR imaging of brain atrophy,
or other assessment of AD or other cognitive pathology; the texture
power distribution vs. k-value at various locations in liver can be
compared with other inferences of liver disease, such as biopsy,
physical exam, blood test, MR imaging, or MRE, over a huge
population; use of machine learning over large populations enables
determination of specific biomarkers in pathology; the ability to
make useful correlations using big data and machine learning gets
much better with high SNR measure input such as that provided by
the method of the embodiments disclosed; use of machine learning
can indicate, for example, if a disease is defined by appearance of
a strong signal at a specific k-value appearing in the diseased
tissue.
In advance of the macroscopic pathology attendant with disease
development, pathological changes occur near the cellular level in
affected tissue. For instance, in bone diseases, fracture is often
the downstream effect of ongoing progressive thinning of the
trabecular elements. In soft tissue diseases, such as liver
disease, fibrotic structures develop over a long time in the
affected organ, leading eventually to cirrhosis. And in neurology,
tissue textures in the brain, in both white and grey matter, change
in response to disease onset and progression. The ability to
measure the early-stage changes in disease, those affecting fine
tissue textures, will enable early stage diagnosis, thus enabling
earlier treatment, subject targeting for trial inclusion, and
sensitive monitoring of therapy response.
The embodiments herein enable this direct and sensitive measure of
disease, through their ability to provide clinically robust measure
of the pathologic changes in tissue textures attendant with disease
onset and with early-stage progression, providing the needed
diagnostic capability.
One of the most valuable features of the disclosed method is that
it can be used in conjunction with most contrast methods applied in
MRI. As the method results in a texture measurement, as opposed to
an image, it needs only to have contrast between the tissue
textural elements. This contrast can be generated in many ways,
selected to optimize tissue contrast in specific pathologies. The
tissue texture measurement yields high spatial resolution due to
its high immunity to subject motion. As the acquisition time for
the methods previously disclosed herein is short, the textural data
can be acquired interspersed with image acquisition in various
sequences.
For instance, in bone, for which there is effectively no signal
from the trabecular bone elements themselves, a standard T1 pulse
sequence, which yields high signal from fat, provides the requisite
high contrast between bone and marrow. Thus, the texture
measurement employing the methods herein can yield high sensitivity
in bone when applied with T1 contrast. T2 contrast can be used to
highlight fluid towards determining if a bone lesion is lytic or
sclerotic, as there may be little fat remaining around the
calcified bone to provide signal. T2 weighted imaging has a host of
applications, including abdominal lesion imaging, imaging of iron
deposition in the brain, and cardiac imaging, hence use in
conjunction with the methods previously disclosed herein enables
highlighting of tissue texture in these organs/pathologies.
MRI contrast generation has become increasingly sophisticated over
time. In addition to exogenous contrast agents, such as gadolinium,
there are the standard T1, T2, T2*, proton density contrast, and
Inversion Recovery sequences. Several techniques can be used for
fat suppression in imaging. Many new contrast techniques, often
dependent on functional contrast, have been developed to highlight
different tissues involved in pathology. MR angiography, a method
of visualizing vasculature and blood flow, makes use of MR signal
saturation, or induced phase contrast in flowing blood, to assess
vascular density and permeability. BOLD (Blood Oxygenation Level
Dependent) contrast uses metabolic changes in blood to image active
brain regions. Diffusion weighting, both DWI (Diffusion Weighted
Imaging) and DTI (Diffusion Tensor Imaging), is used to assess
pathology in an increasing range of diseases, providing a signal
reflective of the microscopic state of the targeted tissue. ASL
(Arterial Spin Labelling), traces the diffusion of
magnetically-labelled blood (endogenous contrast) through the brain
to assess pathology; perfusion imaging is used to assess blood
microcirculation in capillaries, another measure of functional
response. In both these contrast schemes, the time-course of blood
flow, is followed to assess the state of the vasculature near a
tumor, as this is a key feature in the diagnosis of gliomas and
other tumors. Blood vessels are present in higher numbers within,
and surrounding tumors than in normal brain tissue, and they tend
to have a larger blood volume. Higher-grade tumors also tend to
have higher blood volume, and the degradation and remodeling of
extracellular matrix macromolecules results in loss of blood-brain
barrier integrity, which is seen as contrast leakage. These
measures can capture the degree of tumor angiogenesis, an important
biologic marker of tumor grade and prognosis, particularly in
gliomas. Application of the methods disclosed herein near the peak
of the signal contrast would provide a direct measure of the
density and size of blood vessels providing direct measure of the
fine-scale vasculature texture as correlational data robustly
measuring the degree of angiogenesis within or in the vicinity of
the tumor. Combined in this way, a robust measure of pathologic
vasculature development for staging neuropathology such as stroke
and tumor can be made.
As an example, diffusion weighting in its simplest form, DWI, uses
the random Brownian motion of water molecules to generate contrast
in an MR image. The correlation between pathology (histology) and
diffusion is complex but, generally, densely cellular tissues
exhibit lower diffusion coefficients. Obstacles such as
macromolecules, fibers, and membranes also affect water diffusion
in tissue. Water molecule diffusion patterns can therefore reveal
microscopic details about tissue state. By measuring the
differential rate of water diffusion across a region of tissue, a
map of diffusion rates, reflecting local pathology, can be
produced. Diffusion weighting is particularly useful in tumor
characterization, vasculature typing, and diagnosing/monitoring
cerebral ischemia, among other pathologies. Ischemic infarcts
within the brain, abscesses, and certain tumors result in highly
restricted diffusion; cysts and edema offer little restriction to
diffusion.
Diffusion imaging presents several problems with data
interpretation, the most salient of which are: 1) the long
diffusion gradients increase the echo time, TE, reducing SNR, 2)
the high diffusion gradients required result in eddy currents in
metal surfaces in the scanner, which cause signal distortion, 3)
the low signal amplitude necessitates use of a relatively large
voxel, on the order of 2.5 mm on a side, hence low resolution, 4)
the sequence, by design, is highly sensitive to motion, so data
recording must be very fast; hence, the ability to increase SNR by
averaging signal from multiple acquisitions is limited.
Additionally, as at least six different directions are needed to
determine fractional anisotropy (FA) the motion sensitivity can
lead to difficulty in data interpretation across the course of the
acquisition. 5) Interpretation of diffusion weighted signals is not
straightforward. The measured diffusion coefficients can arise from
many sources, as the exact mechanisms governing water diffusion
processes in tissues, especially in the brain, are not clearly
understood. What is inferred from the measurement regarding the
barriers and restrictions to free diffusion is based on certain
assumptions about the underlying tissue pathology. This can take
many forms, involving cell membranes, organelles, cell spacing,
axon density, glial density, myelin state, etc. 6) Each DWI voxel
represents an average, the standard voxel size being on the order
of 2 to 2.5 mm on a side. In order to interpret changes in the
Average Diffusion Coefficient (ADC) within the voxel, certain
assumptions are made, such as tissue homogeneity and type of
structure causing the diffusion variation.
The methods disclosed herein entail acquisition within either a
single VOI or within multiple, interleaved VOIs, within one TR.
Data is acquired without use of a spatial encoding gradient to form
an image. This significantly shortens the acquisition time and,
combined with the narrowly targeted acquisition in k-space, enables
acquisition of the requisite data fast enough to provide immunity
to subject motion. Though multiple measures of single volume
acquisition can be mapped across the anatomy under study, each
measure is acquired rapidly within a single volume. High SNR is
assured by this single volume technique as, before motion effects
set in, there is time for repeat measure of each targeted k-value;
the VOI moves along with subject motion when acquiring data across
a single TR. The number of repeats and number of/range of k-values
for which data is acquired is limited by the requirement to keep
the acquisition fast enough to provide the requisite motion
immunity.
The high motion sensitivity of standard DWI, the fact that it is an
indirect, or inferred, measure, and its low SNR combine to make it
not as robust a measure as would be desired in a clinical setting.
Use of the embodiments disclosed herein for data acquisition when
using diffusion contrast can mitigate the motion problem as, though
the echo time is still long, data acquisition is fast enough that
the motion blurring of the signal is minimized. Further, additional
data can be acquired by the disclosed methods during the scan,
relying on contrast such as T1 or T2 weighting. The standard DWI
images, diffusion weighted acquisition by the methods disclosed
herein, and data acquired by those methods using contrast, can all
be input into a machine learning algorithm, to determine
correlation between the measures, and to correlate all three
measures against pathology data and outcomes. Though correlation
with outcome data takes time, it will provide the best assessment
of the capabilities of the embodiments disclosed. Two possible ways
to combine the embodiments disclosed with contrast mechanisms, such
as diffusion weighting, which, in addition to changing the timing
of the elements of a pulse sequence, add extra RF and/or gradient
pulses: 1) acquisition of, for example, a diffusion weighted
intensity in a single voxel, or in a region mapped by voxels which
region is then overlaid by the textural measures obtained using the
embodiments disclosed with any other standard contrast weighting,
or 2) use the novel contrast mechanism, such as diffusion
weighting, to provide contrast for acquisition of the textural
measures using the embodiments disclosed. This acquisition can be
done in a single VOI or, again, in VOIs across a region of
tissue.
Due to the long echo time and sensitivity to patient motion, most
diffusion weighting is done using fast Echo-Planar Imaging pulse
sequences to provide relatively fast data acquisition. However,
chemical shift artifact is highlighted by single shot EPI (around
10 pixels of shift).
Further, as there is not much motion of water through fat,
resulting in a bright DWI signal that can obscure lesions, fat
suppression is often used as part of the DWI data acquisition.
In one embodiment of the methods disclosed herein described in
greater detail subsequently, crusher gradients are used on either
side of the 180.degree. gradients to eliminate focusing of noise
signal generated during the 180.degree. pulse. Replacing these
crusher gradients with diffusion weighting gradients, allows
acquisition of both the diffusion weighted signal as well as the
subsequent restricted k-value signals. As such, the diffusion
weighting would be a measure in the VOI.
DTI (Diffusion Tensor Imaging)--in highly oriented tissues, such as
nerves and white matter tracts, diffusion occurs preferentially
along one direction, diffusion along the nerve/axon tracts being
much preferred to that of the across-track orientation. The degree
of directionality, or anisotropy, in tissue is an indicator of
pathology, as many neurologic conditions degrade the order of
neurologic structures, such as the minicolumns ordering of cortical
neurons, or lead to order degradation through demyelination of the
axons that form the white matter tracts in the brain. In
anisotropic diffusion, the value of the diffusion constant varies
with direction. As this anisotropy is a measure of pathology
advancement, measurement of the diffusion constant in multiple
directions can be used to yield the "fractional anisotropy" arising
from the tissue structures and hence provide a measure of pathology
advancement. In practice, at least six non-collinear gradients are
used to measure fractional anisotropy, leading to a symmetric
9.times.9 matrix, the "diffusion tensor", the eigenvalues of which
yield the major diffusion axes in the 3 orthogonal directions.
Along with using the anisotropy of diffusion to diagnose and
monitor pathology in the brain, the diffusion tensor mapped across
the brain can be used to delineate the path of white matter tracts.
This is called tractography. A possible application of the methods
disclosed herein is to measure texture in the white matter tracts
affected in multiple sclerosis (MS) using standard T1 or T2
contrast or using the embodiments disclosed in conjunction with
diffusion weighting to determine anisotropy of the measure for
correlational input for machine learning with standard DTI
acquisitions.
The methods disclosed herein provide the ability to obtain tissue
texture using contrast that may be applicable to the particular
tissue form being examined A contrast is applied using any one of
the previously described mechanisms enhancing the contrast between
the component tissue types in a multiphase biologic sample being
measured. As described subsequently in greater detail, the contrast
mechanism and its application may occur at various locations within
the NMR inducing pulse sequence. Using pulse sequencing such as
that described with respect to FIGS. 3 and 8 a volume of interest
(VOI) is selectively excited employing a plurality of time varying
radio frequency signals and applied gradients. An encoding gradient
pulse, as also previously described with respect to FIGS. 3 and 8,
is applied to induce phase wrap to create a spatial encode for a
specific k-value and orientation, the specific k-value determined
based on anticipated texture of the tissue within the VOL A time
varying series of acquisition gradients is initiated to produce a
time varying trajectory through 3D k-space of k-value encodes as
previously described with respect to, for example, FIG. 8, 11, 16
or 18, with the k-value set being a subset of that required to
produce an image of the VOL Multiple sequential samples of the NMR
RF signal encoded with the specific k-values are simultaneously
recorded. The recorded NMR signal samples are then post-processed
to produce a data set of signal vs k-values for the k-values in the
set determined by the trajectory.
A first tissue for application of the methods herein is bone.
Though the effect on quality of life is huge, no accurate and
non-invasive method for sensitive assessment of bone fracture
likelihood exists. The current gold standard measure, DEXA, which
relies on x-ray absorption, measures areal density of bone. The
main determinant of bone strength which predicts fracture, is
trabecular microarchitecture, a measure of which is not currently
available in vivo. The embodiments disclosed enables this
measure.
Bone degradation occurs due to several factors, including disease,
cancer therapy, eating disorders, and aging/life style. As
trabecular structure erodes in bone, three main morphometric
figures vary--the trabecular element thickness, TbTh, the repeat
spacing of trabecular cells, TbSp, and TbN, the trabecular number,
which is a redundant figure that can be determined from TbSp and
TbTh. TbTh decreases continuously with bone degradation.
Eventually, as the trabecular elements, or struts, break, there is
a discontinuity in the local value of TbSp. Bone degrades
anisotropically over time, the anisotropy driven in large part by
the effect of load bearing stresses. With progression of bone
disease, the TbSp increases faster along the primary load bearing
direction than it does normal to this direction, the variation
between the two measures being a marker for bone degradation. In
addition to the developing anisotropy of bone morphometry,
variability in the measure of the trabecular spacing, TbSp,
increases, due to the thinning of the trabecular struts to the
point where they break, causing discontinuities in the measure of
TbSp.
The most definitive measure of bone health is the thickness of the
trabecular elements, which is currently impossible to measure
directly in vivo, due to the spatial resolution required of the
measure.
The embodiments disclosed enable this measure, as it provides the
needed resolution for measuring TbTh in thinning trabeculae, down
to tens of microns, near the range where the sudden discontinuities
in TbSp can then be measured to assess further degradation. As the
trabeculae thin to the point of breaking, a sudden shift to
increasing TbSp should be visible in the signal distribution vs.
k-value, due to the breaking trabecular elements. Additionally, the
degree of anisotropy of TbSp can be used as a correlative measure
for fracture likelihood Data can be acquired using the embodiments
disclosed by positioning the VOI within the targeted bone region,
acquiring data within a single TR or across multiple TRs to enable
acquisition across the pertinent range of k-values spanned by TbTh
and TbSp. Data acquired quickly within one TR can be averaged to
improve SNR, the only requirement being that the data is acquired
from similar bone tissue.
The requisite contrast is between bone and marrow. T1 weighting
provides high signal in marrow, bone offering negligible MR signal.
Alternatively, an IR sequence, which results in heightened T1
contrast, can be used. Some work has been done using diffusion
weighting to image bone--this is a possible contrast mechanism when
using the embodiments disclosed.
In healthy bone, TbSp and TbTh are closer in magnitude than they
are in diseased bone. This can be seen in FIGS. 22A and 22B, by
comparing the image of healthy bone, FIG. 22A, with the image of
highly osteoporotic bone, FIG. 22B. The exact form of this
relationship varies somewhat, the difference in these two
morphometric parameters being higher in spine, for instance, than
in the hip across pathology. The increasing difference in measure
of these two morphometric parameters provides a marker of disease
development.
Because of this increasing separation of the two measures, to
measure both TbSp and TbTh in osteoporotic bone involves acquiring
signal data in two spatially separate regions of k-space. In
healthy bone, if gradients are used to select a region in k-space,
it may be possible to define a region that encompasses both TbTh
and TbSp in the distribution of signal vs. k-value in some skeletal
regions. With progressing bone disease the variation in the
measured values of TbSp becomes wider, as does the percentage
variation of TbTh; additionally, TbSp becomes larger (wider
spacing) with disease progression, and TbTh comes narrower. Hence,
the center of each of these distributions separates progressively
with increasing pathology. Using either gradient on or gradient off
acquisition, broadened by gradient height or VOI windowing, or a
combination of the two, the general shape of these distributions
can be determined. These broadened distributions can be used in
real time to determine the regions of k-space to sample more finely
in successive TRs.
As desired, data can be acquired using multiple interleaved VOIs
within each TR. This method allows determination of the variability
in signal at specific k-values within a region of bone. The data
acquired from the different VOIs can be mapped, a value/color/icon
assigned to signal or peak k-value in the distribution, or to the
difference between the k-values associated with, respectively, the
peak position of TbTh and that of TbSp. The specific k-value and
k-value set established by the time varying gradients may encompass
a range of TbSp and TbTh from 0.01 mm to 5 mm in exemplary
applications.
The methods disclosed herein can be applied within and around the
location of a bone lesion identified with, for example,
conventional T1, T2 or proton density contrast, or flow or
diffusion contrast MR imaging, to assess the state of the
trabecular bone in the region. What is of interest here is a
determination of the lesion type; is the lesion indicative of an
erosive tumor, or is the lesion in a region of
inflammation/degraded bone surrounding a fracture. Some lesions are
dangerous and erosive tumors, some lesions are benign. Acquiring
data by the embodiments disclosed in multiple VOIs in the area of
the lesion would enable a determination of whether the trabecular
structure is degraded in the vicinity, and how progressed the
degradation is, both spatially and temporally. Further biomarkers
can be derived by inputting the MR images of lesions to machine
learning algorithms and correlating them with the trabecular data
of TbTh, TbSp, TbN, anisotropy and measure variability. By this
novel method, the diagnostic content of MR images can be improved,
as the appearance of the lesion on the image can be tied to a
specific degree of bone pathology.
T2 contrast can be used in conjunction with the embodiments
disclosed to highlight fluid in an oncological bone lesion to type
it as either lytic or sclerotic. In such pathology there may be
little fat/marrow remaining around the calcified bone to provide
signal. In an oncologic bone lesion there is usually a mix of
fluid, and of marrow in various states of inflammation. To yield a
signal from outside the hard bone, proton density can be used.
Alternatively, diffusion weighting would return signal based on
diffusion of water molecules in the fluid imbued marrow phase.
Use of the embodiments disclosed to acquire signal vs. k-value data
in bone, applying the various methods disclosed above, yields
several biomarkers for assessing bone health. Measurement of TbSp,
TbTh, and TbN in multiple VOIs at different locations in the bone,
and with different orientations of the textural encode gradient,
yields information on the magnitude and variation of the
morphometric parameters, their variation with direction relative to
the load bearing axis of the bone, and the variability in the
measures locally and across larger bone regions. While, for
instance, a measure of TbTh in one orientation locally in advanced
disease will clearly reflect pathology, a more sensitive marker for
bone health can be derived by combining the sum of the data
acquired.
However, correlational data is required for feature/biomarker
development or extraction. The highest content predictor of
fracture likelihood is fracture history. Bone biopsy is also very
sensitive but, as it is a highly invasive biomarker, this procedure
is rare. Though DEXA is the current gold standard for bone health,
it measures areal bone density, and is not sensitive to trabecular
architecture; hence, it is at best a mediocre predictor of fracture
likelihood. However, with a large enough sample, this metric can
provide increased correlation for diagnostic definition. Taken
together, DEXA data and patient fracture history provide a
high-level learning framework for correlation with the entirety of
the output data derived by the embodiments disclosed, enabling
definition of a sensitive diagnostic tool from the embodiments
disclosed.
Rather than try to derive biomarkers from the acquired data by
individual comparison to look for feature extraction, machine
learning algorithms will provide the best correlational data
between multiple measurements and, when used in an unsupervised
mode, can be compared to extract features from the data for
biomarker development.
Further, besides correlation between TbTh, anisotropy data, and
measure of TbSp and its variance, fracture data from subjects will
be correlated with these measures, also using machine learning
algorithms, to develop markers for fracture likelihood. Biomarkers
can be derived directly from the signal vs. k-value data by
inputting it into machine learning algorithms and correlating it
with, for instance, fracture occurrence data from the same patient,
DEXA measurements, or bone biopsy report data.
Liver tissue or other tissues subject to fibrotic invasion provide
a second example of the use the disclosed embodiments. Although the
underlying causes of liver disease are complex and varied, the
salient feature of the disease is the development of fibrotic
depositions within the liver. Disease onset and progression are
marked by increasing accumulation of proteinaceous deposits, mainly
collagen fibers, on the hepatic structures. Though fibrotic
development can, in the short term, promote healing, if the disease
is left untreated, the healing response itself becomes a problem,
the excess of proteinaceous substance impeding the normal
functioning of the organ. In the case of liver disease, this
process, left unchecked, advances to cirrhosis--with attendant
carcinoma and/or liver failure. For this reason, diagnosing liver
disease early on, when a range of management options are available,
is optimal. Use of the embodiments disclosed to assess
disease-induced pathologic changes to liver tissue would provide a
low-cost, non-invasive, fast add-on to a routine MR exam that would
be ordered to check liver health. While the focus here is on liver
fibrosis, the pathology, and the application of the embodiments
disclosed, is similar to that of a range of diseases characterized
by fibrotic invasion. A partial list of these diseases--cardiac
fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis,
pancreatitis, kidney disease. Additionally, pathologies such as
prostate disease, lose proteinaceous deposits in response to
disease progression. Though the mechanism is reversed, the tissue
texture assessment needed for diagnosis and monitoring is the
same.
Though biopsy is the current gold standard for liver disease
diagnosis, sampling errors within an organ, significant read
errors, and non-negligible morbidity, and even mortality, make this
other than an optimal diagnostic. For sufficient statistics, many
samples would be required, given the high spatial variability of
fibrotic development within the liver; however, only a small number
of samples can be taken due to the highly invasive nature of the
biopsy technique.
Though what is needed is an accurate assessment of the advancement
of fibrosis, currently nothing exists that can measure this
directly, aside from pathology. By the time liver disease is
diagnosable with liver function tests, ultrasound, or MR imaging,
it is well advanced. What is needed is a diagnostic that can track
the development of the disease in the early stages, when it is
still reversible. Application of the embodiments disclosed to
measurement of fibrotic structure offers a direct and non-invasive
measure, enabling multi-sample, longitudinal monitoring of disease
onset, progression, and response to therapy.
In liver, as in other fibrotic diseases, collagen accumulates in
specific patterns within the organ, "decorating" the underlying
structural elements. Liver tissue is composed of a multiplicity of
adjoining units, or "lobules", the structure of which is delineated
by a central vein, and portal veins that form in a hexagonal
pattern around it (see diagram below). As such, in the healthy
liver (absence of fibrotic development=F0 stage) the salient
dimensions that would appear in a signal distribution of tissue
texture feature sizes arise from the spacing between these
elements--a range of approximately 0.5 mm to 0.7 mm With disease
onset, fibrotic development starts on the portal triads, then
progresses, eventually forming bridges linking the portal triads to
the central veins (Stages F1 through F3). These bridges enlarge and
coalesce, forming islands of regenerative tissue surrounded by
fibrotic deposition. In this process, vessel to vessel structural
spacing in tissue texture becomes gradually replaced by lobule to
lobule spacing (Stages F3 to F4). Thus, a clear marker of disease
progression is the shift in distribution of textural wavelengths
from shorter to longer wavelength (decreasing k-value), this shift
being from about 0.5 mm to about 2 mm, and often longer. As
collagen accumulates on the surfaces of the lobules in response to
ongoing disease, and even the intra-lobule hepatocytes become
decorated, the lobule itself becomes the main textural feature, and
the inter-lobule repeat spacing the salient repeat width in a power
distribution in k-space. This change happens gradually over the
course of disease progression, shifting the power density in
textural wavelengths (inverse k-values) from the healthy range out
to approximately 2-3 mm feature sizes. The salient textural
features involved in this textural wavelength shift are well known
from histology studies.
In order to diagnose liver disease in its early stages, the shift
of the signal as a function of k-value from that expected for
healthy liver to longer wavelengths (lower k-values) indicative of
disease onset and progression, can be tracked using the embodiments
disclosed. This measurement at a particular point in time along the
arc of disease progression and response to therapy, can be made
either by acquiring successive samples at individual k-values over
the desired range of textural wavelength or, alternatively, a
gradient can be applied during data acquisition to span the desired
range in k-space. A hybrid combination of these two acquisition
methods can also be used.
Contrast between the collagen decorating the various hepatic
structures and the underlying tissue can be achieved using either
endogenous or exogenous contrast: signal from fibrosis is dark in
standard T1 imaging, and can be bright in T2 imaging, due to the
large water content in the fibrotic structure. Use of Gd contrast
agent shortens T1 such that on T1 weighting the fibrosis shows up
bright against the background tissue. Higher contrast makes for a
more robust measure. However, although these contrast mechanisms
provide contrast between fibrosis and underlying tissue, standard
MR imaging is not capable of sufficient resolution to discern the
pattern of fibrotic development on the various hepatic structures,
which characterizes early stage disease. Patient motion blurs the
image, even when using breath-hold imaging or respiratory
triggering. Using standard MR imaging, liver disease can only be
assessed at the more advanced stages, when the liver may be
irreversibly damaged. Though advanced disease is diagnosable, what
is needed for therapy justification and response monitoring is
early stage diagnosis.
Diverse MR imaging based techniques have been used in assessment of
liver fibrosis, besides conventional T1 and T2 contrast with or
without contrast agents. MRE (Magnetic Resonance Elastography),
diffusion-weighted imaging (DWI), and MR perfusion imaging, can
yield some information on liver disease, though none are capable of
robust diagnosis in the earlier stages of the disease. A major
difficulty with them is that they rely on surrogate markers for
fibrotic development. MRE relies on stiffness measurement,
perfusion imaging measures blood perfusion parameters, DWI
(Diffusion Weighted Imaging) measures the ADC (Apparent Diffusion
Coefficient) of water in the liver tissue. These parameters all
vary in response to many factors besides fibrotic development, such
as inflammation, portal hypertension, steatosis, edema, iron
overload, and hepatic perfusion changes. Currently, there is no
direct way to measure fibrotic development in early stage disease.
By providing the ability to achieve robust resolution at the
k-values pertinent for measuring fibrotic development, using
standard MR contrast methods, the embodiments disclosed enables
assessment of disease state in early stage liver disease.
One of the features of the embodiments disclosed that makes it
novel, is that it can be used in conjunction with most contrast
mechanisms. One application of this method is its use in
conjunction with diffusion weighting, using diffusion-weighted
contrast (see FIG. 23 below), but acquiring signal only in the
k-value ranges of the fibrotic deposits in early stage disease
rather than the entire image acquired in standard DWI. By using the
embodiments disclosed for signal acquisition, the data is acquired
with a much finer spatial resolution than is possible with
diffusion-weighted MR imaging. The texture being measured is on the
scale of the fiber-decorated structures, between actual fiber
clumps, rather than an averaged measure affected by partial volume
imaging. Fibrotic deposition lowers the diffusion coefficient for
water, the lower ADC (apparent diffusion coefficient) in areas of
fibrosis making for a brighter signal than the surrounding tissue.
By using diffusion weighting in conjunction with the embodiments
disclosed the structural signal obtained will measure highly
localized water diffusion. Hence, as the lobular unit transforms
from one with no delineated boundaries to collagen decoration of
the hexagonal boundary and then to filling in the entire lobule,
water diffusion at the boundaries will be impeded, increasing
diffusion weighted signal intensity. As pathology increases, then a
textural signature can be obtained by using diffusion contrast. Two
approaches to positioning of the diffusion weighting gradients are
as shown in FIGS. 24 and 25. The shown pulse sequence for selecting
the desired VOI and initial phase wrap for k is as described in
FIG. 3 and is numbered consistently in FIGS. 24 and 25. FIG. 24
shows positioning of the diffusion weighting gradients 2402, 2404
on either side of the second 180.degree. slice selection pulse,
while in FIG. 25, the diffusion weighting gradients 2502, 2504 are
positioned before the first, and after the second, 180.degree.
slice select pulses to provide more diffusion time for the same TE
than would be available when placing the pair either side of the
last 180.degree. slice-selection pulse.
The integrated pulse sequence described with respect to FIGS. 24
and 25 may be repeated with the diffusion gradient applied along
multiple axes, similarly to DTI (Diffusion Tensor Imaging). The
output dataset would then allow development of a diffusion tensor,
enabling determination of the FA (Fractional Anisotropy), a
reflection of water flow pathways in the tissue which reflect
cellular-level changes.
Fibrotic texture development can also be assessed using the methods
disclosed herein in conjunction with contrast, such as T1 or T2
weighting, with or without exogenous agents such as Gd. By use of
localized sampling in both real and k-space, the methods disclosed
herein enables fast acquisition of signal at the requisite
k-values, enabling robust assessment of pathologic tissue texture
at a specific location in the liver--providing a measure of the
textural frequencies present at that location, immune from the
subject motion-induced blurring that limits current MR imaging
methods. Using the methods disclosed herein, the problem of
respiratory motion is circumvented by the speed of acquisition of
the requisite data. To sample pathology variability within the
liver, VOIs 2602a-2602d can be positioned at various locations in
the liver as represented in FIG. 26, using either interleaved
acquisition within one TR, or measurements in separate multiple
TRs. By use of the methods disclosed herein, texture coherence is
maintained within each defined VOI throughout the data acquisition
at specific k-values or k-value ranges, so as to enable SNR
maximization through signal averaging. If desired, repeat sampling
can be made in subsequent TRs at the same location, to obtain an
average measure of the degree of fibrotic invasion at that
location, for assessment of stage of disease progression. All of
the various MR-based measures of fibrotic development in liver
disease can be combined with blood-based, biopsy, MRE, physical
exam data across a population, using machine learning to both
correlate data towards biomarker development for the embodiments
herein for textural measure, as well as using machine learning in
an unsupervised mode applied to the textural data for feature
extraction towards biomarker development.
While the application to liver disease has been called out in some
detail here, assessment of other fibrotic diseases is enabled by
the embodiments disclosed. Fibrotic development is the hallmark of
lung disease (e.g. cystic fibrosis, idiopathic pulmonary fibrosis),
myocardial fibrosis, muscle fibrosis, pancreatic fibrosis and
kidney disease. Additionally, as mentioned previously, some
diseases, such as prostate disease, induce reduction in
proteinaceous deposits.
Lung disease diagnosis is stymied by the large range of forms the
disease can take, each with a different underlying etiology,
prognosis, and required therapy. Idiopathic Pulmonary Fibrosis
(IPF) is a chronic, ultimately fatal disease of the lung
characterized by progressive decline in lung function. Scarring of
the lung and formation of fibrotic tissue in the interstitial lung
spaces between the air sacs are the primary injury associated with
disease development. The peripheral airways and vessels may also be
affected. Diagnosis currently is by ruling out other pathologies,
pulmonary function testing, stress tests, blood gas analysis,
patient history, in conjunction with imaging using High-Resolution
Computed Tomography (HRCT). IPF diagnosis can be confirmed with
lung biopsy, but the histology shows striking variation from one
region to the next leading to high sampling errors. Further, biopsy
is a highly invasive procedure, the tissue insult compounded if
there is need for multiple samples.
IPF is believed to be the result of an aberrant wound healing
process resulting from repetitive injury of the alveolar epithelial
cells. This triggers action of fibroblasts that results in abnormal
and excessive deposition of collagen in the pulmonary interstices,
forming pockets of "ground glass," fibrotic tissue formation,
associated with alveolar degradation. Minimal inflammation is a
defining characteristic of the pathology, distinguishing it from
COPD.
Histologically, IPF is characterized by the presence of differing
proportions of interstitial inflammation, fibroblastic foci, and
established fibrosis and honeycombing, all coexisting with areas of
normal lung parenchyma. This heterogeneity makes diagnosis by
biopsy problematic. Characteristic high-resolution CT (HRCT)
findings of IPF include textural changes, including honeycombing,
and architectural distortion, involving mainly the lung periphery
and the lower lobes. In approximately 50% of cases, HRCT scans are
sufficient to allow a confident diagnosis of IPF, obviating lung
biopsy. In the remaining 50% of patients, the HRCT findings are
relatively nonspecific and may mimic those of other interstitial
lung diseases. Souza et al., "Idiopathic Pulmonary Fibrosis:
Spectrum of High-Resolution CT Findings", American Journal of
Radiology, December 2005
An earlier diagnosis of IPF is a prerequisite for improvement of
the long-term clinical outcome of this progressive disease. When
treated early, IPF has better outcomes than other forms of
interstitial pneumonias. Idiopathic Interstitial Pneumonia can
either take the form of IPF, or can be classed under several other
forms of pneumonia, with various presentations and prognoses. A
major diagnostic need is to differentiate lung disease between IPF
and these other forms of lung disease. The ability to more
sensitively image lung pathology would enable earlier diagnosis, as
well as subsequent therapy monitoring. But the resolution available
from Computed Tomography is limited. Even acquisition during a
single breath hold is severely compromised by cardiac pulsatile
motion and noncompliance to breath hold.
MRI has recently emerged as a clinical tool to image the lungs.
Along with enabling tunable tissue contrast and the ability to
obtain functional information, it is a non-invasive measure,
allowing multiple and repeat measurements. In cases of pediatric
imaging, pregnant patients, or for research purposes, the lack of
need for ionizing radiation makes MRI the preferred modality.
However, the physical properties of lung parenchyma are very
different from those of tissue such as liver or brain. The low
density of the tissue, and the susceptibility differences between
tissue and air, lead, respectively, to very low signal and to rapid
dephasing. This dephasing, resulting from the highly inhomogeneous
local magnetic fields at the edges of parenchyma, results in T2*
values as short as 2 msec or less, at 1.5T. Thus, the pulse
sequences in use rely on GE (gradient echo) refocussing to enable
short TE values. However, the short T2* also allows a brief signal
acquisition. While this is good from the standpoint of resolution,
the recorded signal is low, making MRI of lung parenchyma highly
challenging.
CT cannot resolve the underlying structure of the ground glass
regions that appear on imaging of diseased lung tissue.
A clear indication of pathology is the appearance of regions within
the lung that have a hazy, mottled, appearance, often termed
"ground glass" pathology. In some types of lung disease, under the
general term COPD, the appearance of this patterning in the lung
tissue is associated with inflammation. In IPF, it is associated
with development of fibrosis in the alveoli. Though the fine tissue
textures underlying the macroscopic appearance in imaging of ground
glass regions can help distinguish the various forms of pathology
and help set therapy, neither MRI nor CT offer the requisite
resolution. This distinction can, however, be made using the
embodiments disclosed.
At the microscopic scale, tissue changes associated with
inflammation in lung disease are relatively homogeneous within the
cloudy patches, showing no spatial texture on the sub mm scale.
IPF, however, a disease presentation that usually occurs with
minimal associated inflammation, displays at the microscopic scale
a mottled textural signature, with a repeat on the order of 0.5-1
mm Though the signal from the fibrotic collagen development that
causes this texture is low, contrast between the collagen, which
contains fluid, and the underlying lung tissue, which is very low
density being mainly air sacs, enables imaging. Hence, as part of
an exam workup, the embodiments disclosed can be used as a
microscope to reveal the fine textural signature underlying the
macroscopically revealed pathologic regions within the lung.
As a non-invasive measure towards determination of lung disease
type, the embodiments disclosed would provide data on a scale
unachievable through imaging. Combination via AI/machine learning
algorithms with current diagnostic measures--pulmonary function
testing, stress tests, blood gas analysis, patient history,
imaging, and, if applied, biopsy--would enable biomarker extraction
from the embodiments disclosed, and calibration of the varying
textural signatures embedded in the data set.
Measure of the healthy alveoli using the embodiments disclosed
would be difficult, due to the fact that the alveolar walls are on
the order of 10 .mu.m, the center of the air sacs generate no
signal, and the susceptibility difference at the air wall interface
would lead to very rapid dephasing. However, when AI/machine
learning algorithms are used to optimize data interpretation, as
above, there is a clear chance that the embodiments disclosed could
be used for direct measure of the alveoli, and the textural
variation inherent in disease progression.
Further, towards diagnosis of lung cancer, the embodiments
disclosed can evaluate the state of vasculature in the vicinity of
lung nodules, suspected of malignancy. Current use of CT to
evaluate lung nodules in high-risk populations has been found in
recent analysis to have a false positive rate of over 97%, leading
to unnecessary follow-up procedures and concern. Castellino, "Lung
Cancer Screening--Benefits Few, May Harm Many", Medscape Jan. 30,
2017.
While the lung moves significantly during free-breathing, and even
breath-hold motion is large compared to the very fine textural
features that can discriminate disease forms, the embodiments
disclosed are immune to this motion, once the VOI is defined. The
speed of data acquisition with the embodiments disclosed (<1
minute), combined with the ability to run the method in a
free-breathing mode, makes the procedure easy to incorporate in a
standard MR lung scan. Wild et al., "MRI of the lung" (1/3),
Insights in Imaging 2012.
Given the myriad forms of lung disease manifestation, and the need
to distinguish them in order to determine appropriate therapy and
monitor response, more information on pathology is needed. While
there are several symptomatic level tests, medicine weights highly
the variability across CT and MR images. However, the ability to
look at tissue changes at the microscopic level, the earliest
harbinger of disease onset, has until now not been available. Use
of the embodiments disclosed provides such capability.
To obtain the most information from this measurement, diagnostic
information obtained by current methods can be used as training
sets by incorporating this data in a machine learning algorithm
together with the data obtained by the embodiments disclosed.
Measures of pulmonary function, stress tests, images, blood gas
analysis, patient history, and biopsy, are all suitable candidates,
though the main driving element of the learning set is disease
outcome when correlated with the new data.
One of the most common histologic features of the failing heart is
myocardial fibrosis, diffuse replacement or invasion of the
myocardium by fibrous connective tissue. This fibrotic development,
which results in wall stiffening, reduced contractility, and
impaired overall heart performance, is a significant global health
problem associated with nearly all forms of heart disease. Cardiac
fibroblasts, an essential cell type in the heart, is responsible
for the healthy extracellular matrix. However, upon injury, these
cells transform to a myofibroblast phenotype and contribute to
cardiac fibrosis, generating excessive deposition of connective
tissue in the interstitial space in the cardiac muscle. Fibrosis
has been shown to be a major independent predictive factor of
adverse cardiac outcome. However, there is a lack of accurate
clinical tools to precisely phenotype patients with heart
disease.
Assessment of cardiac fibrosis can be made by biopsy and staining
techniques. However, biopsy is highly invasive, sampling errors
limit its sensitivity, and the entire left ventricle cannot be
sampled, hence limiting accurate clinical pathology assessment.
Use of cardiovascular magnetic resonance (CMR) for the non-invasive
imaging for patients with compromised heart function has increased
over the last decade. The two main methods currently in use are
Late Gadolinium Enhancement (LGE) MR and T1 mapping, also based on
Gd contrast.
LGE of myocardial fibrosis is based upon the prolonged washout of
Gd that results from the decreased capillary density within the
myocardial fibrotic tissue. The increase in gadolinium
concentration within fibrotic tissue causes T1 shortening which
appears as bright signal intensity in the CMR image based on
conventional inversion-recovery gradient echo sequences. This
provides discrimination between fibrotic myocardium and normal
myocardium.
In multi-site clinical use, LGE has absolute signal level problems.
Its accuracy for absolute quantitation is limited also due to an
over-sensitivity to image settings such as intensity threshold.
While currently LGE CMR is the most accurate method to measure
myocardial replacement fibrosis, its sensitivity is limited for the
assessment of diffuse interstitial fibrosis.
The second MRI measure of fibrotic development is based on the
variation in post Gd contrast T1 relaxation times that result from
variations in the molecular environment of the water molecules in
tissue. Post-contrast T1 values of scarred myocardium are
significantly shorter than those of normal myocardium due to the
retention of gadolinium contrast in fibrotic tissue. As such, T1
mapping can accurately differentiate pathologic fibrosis from
normal myocardium, and can quantify fibrotic development. T1
relaxation times vary significantly from one type of tissue to
another, but also within the same tissue depending on its
physiopathological status, i.e. whether inflammation, edema, or
fibrosis is present in the tissue under study. Hence, mapping of T1
across a region provides information on the spatial distribution of
pathology. Specific properties of the target tissue determine the
level of T1 shortening induced by the gadolinium contrast agent,
generating specific differences in signal intensity.
However, while post-contrast T1 value of myocardial fibrosis is
significantly different from that of normal myocardium, T1
distribution can be significantly scattered and this limits its
sensitivity for disease states with less severe fibrosis.
Though clinical data to date is scarce, the combined application of
T1 mapping with CMR-LGE may help to provide more precise assessment
of the heath of myocardial tissue, and to stratify cardiovascular
risk in patient populations, detecting subclinical myocardial
changes before the onset of serious heart dysfunction. But the
shortcomings of these techniques, combined with the recent
reticence to inject Gd due to its retention in the brain, make the
potential role of the patented method in assessment of myocardial
fibrosis timely. The embodiments disclosed can provide the fine
tissue characterization that will help improve therapeutic
strategies and enable a more direct monitoring of their effect,
thus improving clinical outcomes. Such enhanced measure would
assist in the search for much needed therapies.
Further, spatial resolution of the amount of cardiac fibrosis in
early stage heart disease using MRI is seriously hampered by
cardiac pulsation over the time of the measurement. As motion is,
unlike Gaussian noise, a non-linear effect, it can't be averaged
out--there must be sufficient signal level to allow reregistration
before averaging for electronic noise-reduction. A more sensitive
(higher SNR), non-invasive technique, capable of assessing textural
changes throughout the range of development of cardiac fibrosis,
from onset to advanced pathology, is needed to enable diagnosis and
monitoring of therapy response. The embodiments disclosed provide
this capability Travers et al., "Cardiac fibrosis--the fibroblast
awakens", Circulation Research, March 2016; Bronnum and Kalluri,
"Cardiac fibrosis: cellular and molecular determinants", Chapter 29
of Muscle, Vol. 1; Konduracka et al., "Diabetes-specific
cardiomyopathy in type 1 diabetes mellitus: no evidence for its
occurrence in the era of intensive insulin therapy". European Heart
J. 2007; Mewton et al., Assessment of myocardial fibrosis with
cardiac magnetic resonance, Journal of the American College of
Radiology, February 2011
MRI of the heart enables multiple and repeat measurements to track
therapy response. Pertinent morphological information, such as wall
thickness, edema, scarring of the myocardium, and perfusion (e.g.
at rest and during stress) are all macroscopic measures of health.
The basic imaging protocols to obtain these measures, such as LGE
and T1 mapping, have helped to establish CMR. However, a figure
that is missing from current diagnostics is the ability to track
the onset and progression of pathologic changes at the microscopic
level, specifically the development of fibrosis within the
heart.
To provide a much stronger diagnostic for heart disease, the data
sets from both techniques can be combined. Use of the embodiments
disclosed would allow direct measure of the fine texture signature.
While it could be used in conjunction with T1 decay/Gd injection
measures, the recent push to eliminate use of Gd may make use of
endogenous contrast, such as T1, IR, and diffusion weighting,
necessary. T1 mapping data, again using either Gd or endogenous
contrast can be compared to the textural measures acquired in
multiple VOI positioned to cover the same area as that mapped.
Application of the two techniques as interleaved sequences would
ensure that the two measures are acquired at the same tissue
location. In this way, the textural signal acquired by the
embodiments disclosed can be compared with the T1 mapping, enabling
determination of both the direct textural measure and the molecular
environment, both measures providing assessment of the level of
pathologic fibrotic development. The data from the two techniques,
along with other measures of cardiac function from physical exams,
serum concentrations of collagen-derived serum peptides, as well as
quantitative analysis of echocardiograms can together be fed into
machine learning algorithm, providing a much clearer assessment of
disease progression and therapy results.
Gd-based LGE could provide a third layer of assessment of the
developing pathology. For combination with the other diagnostics
for optimization of information extraction by machine learning.
This combination of techniques, given the high-resolution direct
measure provided by the patented method, can provide an enhanced
assessment of disease development, enabling therapy response
determination and disease prognosis.
Prostate cancer is the second most common cause of cancer death in
American men. In current practice, prostate biopsy exams are
recommended for men for whom blood tests show high prostate
specific antigen (PSA) serum levels, or who demonstrate other
symptoms related to prostate dysfunction on exam. Biopsy is
painful, risks serious complications such as infection and
bleeding, and is diagnostically fraught due to read and sampling
errors. The procedure involves twelve needle samples, taken at
random from the prostate using trans-rectal ultrasound (TRUS)
guidance. Often several tumors of various sizes are present in the
organ. Due to the random nature of the sampling, a tumor may not be
intersected by any of the needles, making it problematic to
quantify aggressiveness of suspected cancer. TRUS-guided needle
biopsy misses 25% to 30% of clinically significant tumors because
anterior prostate cancer lesions are occluded, making detection
difficult until the tumors are quite sizeable. 3 MRI can help avoid
unnecessary prostate cancer biopsies, AuntMinnie com Jan. 25, 2017
http://www.auntminnieeurope.com/index.aspx?sec=sup&sub=mri&pag=dis&ItemID-
=6139 26; 4 El Sevier, Ltd. open access articles, H. U. Ahmed et
al., Jan. 19, 2017,
http://dx.doi.org/10.1016/S0140-6736(16)32401-1.
Further, the highly invasive biopsy procedure is often prescribed
when there is no cancer present--recent research indicates that
over a quarter of the men sent for prostate biopsy did not need the
procedure. Also, men with no cancer, or with benign cancers, are
sometimes given the wrong diagnosis and are then treated even
though this offers no survival benefit and has serious side
effects. Overdiagnosis and overtreatment have increased in
diagnostic practice. A Quarter of Prostate Cancer Biopsies May Not
Be Necessary, Xuan Pham, Lab Roots, January 2017,
https://www.labroots.com/trending/cancer/5107/quarter-prostate-cancer-bio-
psies; 2 Imaging Guided Prostate Biopsies Miss Apical Cancer
Lesions, Medscape 1/25/17
http://www.medscape.com/viewarticle/874873?src=wnl_edit_tpal&uac=156182MR-
. As a result, the US Task Force on Preventive Health Care has
taken the position that the risk from PSA testing outweighs the
benefits. Clearly, additional information is needed here to make
the correct diagnoses and avoid unwarranted and invasive procedures
and treatment.
Recent studies have focused on the benefit of multi-parametric MR
imaging (mp-MRI)--scans that use multiple types of tissue
contrast--before biopsy. mp-MRI has been found to rule out the need
for needle biopsy in as many as a quarter of cases referred for
MRI. When it is used in conjunction with medically necessitated
biopsy, it can correctly diagnose a high percentage of aggressive
prostate cancers, with higher sensitivity than provided by standard
transrectal ultrasound-guided (TRUS) biopsy. An inverse correlation
exists between Gleason score, a marker of tumor aggressiveness, and
ADC (Apparent Diffusion Coefficient, as measured with DWI
(Diffusion Weighted Imaging) in MR. In addition, the mp-MRI scans
also demonstrate ability to more precisely locate and gauge the
size of tumors, improving detection of aggressive cancers. However,
it is often hard to distinguish some benign abnormalities, such as
fibrosis, prostatitis, and scar tissue from lesions.
While combining mp-MRI with biopsy yields better results than does
ultrasound-guided biopsy alone, this is still not 100% accurate. It
is required that men still be monitored after their mp-MRI scan and
biopsy. Biopsies will still be needed if a later mp-MRI scan shows
suspected cancer, but the scan could help to either rule out the
need for biopsy, or guide the biopsy so that fewer and better
biopsies are taken.
Because of the highly invasive nature of biopsy, as well as its
diagnostic shortcomings, prostate care would be progressed if a
less-invasive, high information content diagnostic procedure was
available. As the additional information provided pre-biopsy by
mp-MRI appears to be of clear value, adding high density
information to this procedure would be of huge benefit, as the
patient is already in the scanner.
Accurate tumor localization and typing within the prostate would
enable focal therapies such as cryosurgery, intensity modulated
radiation therapy, brachytherapy, or high intensity focused
ultrasound to ablate just the tumor rather than having to use a
more global therapy. Xu, et al., Magnetic Resonance Diffusion
Characteristics of Histologically Defined Prostate Cancer in
Humans, Magnetic Resonance in Medicine 61:842-850 (2009).
For a patient referred for mp-MRI, in addition to the basic 3
studies--T2-weighted, diffusion-weighted, and DCE (dynamic contrast
enhanced) scan, the embodiments disclosed would be used as
described above, to measure the state of the microvessels across
the prostate, and to measure the tissue texture through the organ,
as this reflects the health of the organ.
Properly implemented, the embodiments disclosed can be used to
provide high value diagnostic information towards localizing and
typing prostate tumors for size and aggressiveness, while
distinguishing them from BPH (Benign Prostatic Hyperplasia), a
common pathology associated with aging. This procedure would
involve both measuring and mapping the density and form of the
microvasculature across the prostate, as an indication of tumor
localization and aggressiveness, as well as an assessment of
pathologic changes in the prostate tissue across the organ.
Mp-MRI uses typically three different contrast mechanisms--T2
contrast, diffusion-weighted contrast (DWI) and DCE, which follows
the time course of the tissue image following injection of an
exogenous contrast agent such as gadolinium. Higher resolution
measurement of the microvasculature can be provided by using the
embodiments disclosed in conjunction with the mp-MRI DCE measure.
As data acquisition using the embodiments disclosed is extremely
fast, data to map the high-resolution micro vessels across the
organ could be acquired as part of the DCE sequence.
Additionally/alternatively endogenous flow contrast, such as
arterial spin labelling, could be used to provide contrast to the
vessels for measure of their volume, density and sizes across the
organ.
As discussed previously, one of the features of the method is its
ability to be used in conjunction with most any contrast mechanism,
thus enabling high resolution measure of the tissue textures
brought into relief by the contrast. The speed of the measure,
along with the fact that the targeted volume of interest (VOI) can
be sized and moved as desired, enables coverage of the entire
prostate in a <1-minute exam, allowing assessment of changes in
the micro-vasculature and matrix tissue with disease progression.
T1, T2, and DWI contrast can be used in conjunction with the
embodiments disclosed to provide assessment of changes in the
tissue texture across the prostate from the epithelial region and
through the stromal areas. This could replace the need for a
physical biopsy, providing a non-invasive tissue pathology
assessment.
Further capability is provided by use of DTI (Diffusion Tensor
Imaging) contrast for which varying the direction of the DWI
diffusion gradient allows tracking of directional change in tissue
resulting from microscopic changes affecting water diffusion
through the tissue. Use of DTI for application of the embodiments
disclosed, allows assessment of the anisotropy of tissue
changes.
At the microscopic level, normal prostate has a branching
duct-acinar glandular architecture embedded in a dense
fibro-muscular stroma. In prostate carcinoma, tightly packed tumor
cells disrupt the duct-acinar structure leading to the decreased
ADC in tumor due to the cellularity induced diffusion restriction.
The tissue texture in healthy fibrous tissue has a repeat distance
(wavelength) on the order of a few hundred microns, while that in
tumors is on the order of tens of microns. Fine tissue texture is
also visible in regions of BPH on histology, but the overall
patterning is less isotropic and varied in size than that from
tumor regions, an anisotropy that can be measured by varying the
direction of applied gradients used in the measure. Hence, a clear
variation in textural signal is available to differentiate the
fibrous tissue to allow diagnosis of cancerous vs. BPH vs. healthy
prostate. The embodiments disclosed is the only non-invasive
diagnostic capable of directly measuring these tissue
variations.
Benign Prostatic Hyperplasia (BPH) has fibrous, muscular and
glandular components--the fibrous tissue is laid in irregular
patterns, as with the muscular element, giving the appearance of
nodularity. The increased cellularity in the region of tumors leads
to a lowered apparent diffusion coefficient (ADC), a measure
obtained from DWI in the region indicative of development of
prostate cancer. If a form of diffusion contrast which highlights
anisotropy in microscopic components of tissue texture is used to
provide contrast for the acquisition of data by the embodiments
disclosed, FA differentiates stromal from epithelial BPH.
Standard diagnosis of disease state is often made by comparison
between various diagnostic measures, such as symptoms, serum
markers, pathology measures, and patient outcomes. This last
figure, patient outcome, is, of course, retrospective. The huge
increase in processing capability in today's computers has changed
the way this comparison is made, as current electronic storage and
processing capability enable more detailed comparison among
multiple diagnostics. But, more than just using the various
diagnostic measures towards a more robust diagnosis, the ability of
computers can enable maximum extraction of data from new
diagnostics through use of machine learning techniques. In applying
the embodiments disclosed to prostate disease, rather than trying
to extract biomarkers as specific features from the power spectrum
obtained as characteristic of the vessels and surrounding tissue in
the organ, the highest information content can be obtained from the
data by using the entire data set. Anecdotal notes on disease
progression and outcomes, along with diagnostic data obtained from
the mp-MRI scans, can serve as a training set to "teach" a machine
learning computer algorithm to assign a diagnostic meaning to the
data obtained by the embodiments disclosed. stage disease and
diagnose disease progression and aggressiveness. Computers are more
capable of making the comparisons, depending on the huge amount of
information contained in the various data sets to draw conclusions
and stage disease. By this method, the maximum amount of
information can be extracted from the data.
Given the tissue variability across the prostate from the
epithelial to the stromal region, and locally due to developing
pathology/tumors, use of the disclosed embodiments as a diagnostic
such that it covers most of the prostate is best poised to assess
the health of the organ. Hence, the workflow to provide this
disease diagnosis and to track progression would look something
like:
Patients that are in for mp-MRI because of symptoms or PSA testing
indicating suspicion of prostate disease would also be scanned
using the embodiments disclosed in conjunction with various
contrast techniques.
Scout images as described herein may be employed for preliminary
assessment and calibration.
The embodiments disclosed would be used to measure
microvasculature--density, volume, and vessel size, in stepped VOIs
across the prostate, using the exogenous contrast used for mp-MRI,
interspersing this measure with the time course imaging acquisition
done as part of the mp-MRI, or using endogenous contrast such as
ASL, to provide contrast for measure of vasculature.
If the exogenous contrast used in mp-MRI were to be used to
generate vessel contrast for measure by the embodiments disclosed,
mp-MRI and the embodiments disclosed could be interspersed in time
as the contrast reached a maximum and then decreased as the
labelled bolus of blood moved out of the prostate. Otherwise,
endogenous contrast such as ASL could be used for this purpose. As
endogenous contrast does not involve injection of Gd, it is in line
with the non-invasiveness of the embodiments disclosed.
In addition to the other mp-MRI imaging, the embodiments disclosed
would be used to acquire textural signature using T1, T2,
diffusion-weighted contrast, though, as desired, additional
contrast methods could be applied. Gradients for these techniques
would be applied in varying directions, to learn something about
the directionality of the underlying tissue structure as this is a
component in associating structure with pathology.
For each patient, comparison of the data obtained from the various
applications of the embodiments disclosed would be compared with
all other diagnostics to "train" the method to yield the highest
disease-specific information. The various input information sources
include all other diagnostics, such as the mp-MRI data, serum
measures, biopsy, physical exam, ultrasound, CT (Computed
Tomography, and PET (Positron Emission Tomography). In addition,
pertinent patient/disease history would be included in the training
set. By this method, textural signatures specific to an individual
pathology course can be identified.
Many neurologic diseases and conditions have a vascular component
that may serve as a marker for disease onset and progression,
allowing diagnosis and therapy tracking which provides another
exemplary implementation of the methods disclosed herein. The
ability to sensitively assess changes in micro-vessels would enable
monitoring of pathology progression in a number of diseases which
are often not diagnosed until pathology is well advanced.
Angiogenesis, formation of new blood vessels from pre-existing
micro vessels, is necessary for tumor growth and metastasis. Rather
than the ordered formation of vessels that exist in healthy tissue,
pathogenic angiogenesis tends to form chaotic, tortuous vessels,
replete with blocked, dead end structures--see FIG. 23. Vessel
diameter and wall thickness are highly variable in angiogenic
micro-vessels, with marked vessel permeability in places.
For example, tumor aggressiveness is closely correlated with
neovascular density, as angiogenesis is needed to supply the tumor
with oxygen and nutrients. The ability to assess the amount of
angiogenic development at a tumor site, and to characterize the
vascular morphology, would enable assessment of tumor
aggressiveness. By determining the extent of the angiogenic
vasculature within and surrounding the tumor, it is possible to
determine the necessary boundaries for surgical removal. Likewise,
therapy response may be trackable in part by measurement of
vasculature as it reverts to a more normative state. Degree of
angiogenic vasculature development can be assessed to some extent
using serum markers, or by biopsy. But biopsy is highly invasive,
and prone to sampling errors and read variability.
As another example, several forms of dementia, most notably
Alzheimer's disease (AD), are now recognized as having a large
vascular component with pathogenic vessel development. Additional
forms of dementia, such as Huntington's disease (HD), Parkinson's
disease (PD), and Frontotemporal dementia are also found to have
compromised vasculature. In some cases, the salient cause of the
dementia appears to be pathogenic vasculature in the brain, such as
CVD.
Chronic inflammation is another important factor that can lead to
abnormal neurovascular structure, exhibiting permeability and
hemorrhage. Some microvasculature pathogenesis is linked to
permeability of the blood brain barrier. Multiple Sclerosis, a
brain disorder with pathology associated with inflammation and
axonal demyelination, exhibits microvessel disruption. Stroke and
the resultant ischemia result in development of angiogenesis
modifying the capillary network, as the body attempts to heal the
damage. As angiogenesis features increased vascularity, involving
both structural and functional alterations within the neurovascular
system, this increased density, and the high variability in vessel
spacing, is a promising biomarker that can be used for the
characterization of ischemic conditions in the brain following
stroke. For all of these conditions--tumor development, ischemic
stroke, and brain pathology in dementia, a means of assessing the
micro-vasculature in brain tissue, is needed--both for
determination of pathology advancement, and for assessment of
therapy response.
Currently, MRI assessment of the health of microvasculature is most
commonly made by perfusion imaging. Perfusion is the irrigation of
tissues via blood delivery through the microvessels. Because the
state of the vessels changes the dynamics of blood flow, such
measure can be used to assess vascular health. For perfusion MR
imaging, either endogenous or exogenous contrast is used. Exogenous
contrast is most commonly provided by use of Gd-based contrast
agent. Endogenous contrast is obtained through a technique known as
ASL (Arterial Spin Labelling) in which the blood flowing into a
region of the brain is magnetically labelled. In both cases,
sequential images are made via fast imaging techniques, as the
contrast moves into, and exits, the imaging plane. One of the key
features of dynamic imaging, such as perfusion imaging, is that
differential contrast can be obtained via subtraction of the image
obtained with no contrast agent/blood tagging in the imaging plane
from that obtained when contrast is at a maximum in the imaging
plane.
When using a contrast agent for this measure, a bolus of the agent
is injected intravenously and successive images are acquired as the
contrast agent passes through the microcirculation. (Opposite to
what is observed when no contrast agent is used, use of T2
weighting results in dark blood when a contrast agent is used, and
T1 weighting results in bright blood.) In order to enable fast data
acquisition to allow multi-image tracking of the flow before the
contrast agent leaves the imaged tissue region, images are usually
acquired using a variant of the fast MRI acquisition sequence known
as EPI (Echo Planar Imaging). To characterize the state of the
vessels, various flow related quantities are measured: (MTT) mean
transit time through the voxels, time to peak signal, CBF (Cerebral
Blood Flow), and CBV (Cerebral Blood Volume). These quantities,
which vary with vascular condition, are all measurable via
perfusion imaging. In addition to the sequential acquisition of
images obtained while the bolus of contrast agent is present in the
blood, or the magnetically labelled blood is flowing in the imaging
plane when using ASL, at least one image is taken following passage
of the bolus, or of the labelled spins, through the
microvasculature, when contrast between the blood and surrounding
tissue is minimal. This image is then subtracted from the early
images to allow calibration of the absolute signal level from the
microvasculature. Temporal tracking by acquisition of multiple
images enables flow characterization and determination of regions
of compromised vessels.
Angiogenic vasculature is denser, and more varied in vessel
diameter and spacing, than are healthy vessels. The high spatial
variation in vessel thickness and spacing is one of the hallmarks
of angiogenic vasculature and hence, along with increased vessel
density, serves as a marker for angiogenesis-related pathology.
However, image resolution in perfusion imaging is not high enough
to determine detailed vascular morphology. Flow contrast highlights
locally averaged signal variation due to the pathogenic flow
parameters, offering indirect assessment of vessel morphometry.
However, the methods disclosed herein can be used to directly
measure vessel density, and vessel spacing variability, to provide
direct, robust assessment of angiogenic vessel development. Using
the methods disclosed herein to acquire signal vs. k-value data
disclosing tissue texture enables robust resolution of the
morphometric features of the vessels. This acquisition can be done
in one TR, fast enough that the sequence can be injected into the
multi-image-acquisition perfusion series. To provide best
resolution, this morphometry acquisition would be done near peak
contrast, either acquiring data for one TR or for multiple TRs
acquired either sequentially or interspersed at various time points
with the perfusion image acquisitions.
Obtaining a differential measure of the vasculature by the methods
disclosed herein, obtaining signal vs. k-value data both with and
without contrast, provides validation of the origin of the textural
signal as arising from the vasculature. Making these two measures
as close in time as possible allows best spatial and phase
correlative value between the two data acquisitions, to accurately
highlight the signal arising from the vessels.
The best way to keep the time between the two acquisitions short
when using ASL contrast is by 1) acquiring data, by the methods
disclosed herein, in a specified imaging plane with proton density
contrast; 2) immediately following the first acquisition, spin
labelling in a second plane, upstream in the blood flow, in close
proximity to the imaging plane; 3) acquiring spin-labelled data in
the imaging plane, by the methods disclosed herein, the labelling
and 2.sup.nd acquisition as close in time as possible following the
first acquisition. Signal vs. k-value data can be acquired using
either gradient on or gradient off acquisition, or a combination of
the two, to provide measure of signal across the desired span in
k-space
Because the morphometric parameters being measured are expected to
vary significantly, acquisition of signal across a range of
k-values is required, to determine the underlying structural
signature of the vessels. The broadness of the distribution of
signal vs. k-value, and where its peak lies in k-space are the
critical features of interest. The peak assesses the average vessel
density and the broadness assesses the variability of vessel
spacing; both markers for angiogenesis characterization. The
acquisition can be done either with a gradient on or with the
gradient off during acquisition. Appropriate windowing in the
direction of the acquisition axis of the VOI will allow sampling at
a targeted spread of k-values, the exact window function
determining the degree of correlation across the k-value range.
Additionally, hybrid acquisition is possible wherein a gradient is
on for some part of the data acquisition within one TR and off for
part of the acquisition. The aim here is to, while acquiring a
range of k-values, ensure sufficient repeats of, say, a set of
highly correlated k-values, to allow SNR maximization by averaging,
while ensuring fast enough acquisition to provide immunity to
subject motion.
Alternatively, rather than temporally intersperse data acquisition
by the methods disclosed herein into standard perfusion imaging,
the methods disclosed herein can be used in conjunction with any
blood contrast method to measure vessel morphology directly, in
regions exhibiting pathogenic flow parameters. Both vessel spacing
and the variability in this measure are known markers of
angiogenesis, the vasculature spacing becoming more random with
degree of pathology. For contrast, either structural contrast such
as T2 or T1 weighting, which yield, respectively, bright or dark
blood, can be used. Additionally, both black blood and bright blood
flow contrast can be achieved by various standard methods,
including arterial spin labelling. This structural measure of the
vessels can be carried out in as many tissue regions, using as many
acquisition directions, as desired. Angiogenic vasculature would be
expected to exhibit a high degree of anisotropy, so varying the
orientation of the acquisition axis between acquisitions provides
another marker of pathology. Correlation of the flow data from the
perfusion imaging with the structural vessel data from application
of the methods disclosed herein, can be made through machine
learning.
For tracking angiogenesis relating to ischemic stroke, or in the
vicinity of a tumor, acquisition by the methods disclosed herein to
assess the vessel structure, can be carried out in the vicinity of
lesions. To achieve this, a real time response to an imaging scan
that defines the location of these lesions would be used to target
the location for the subsequent vessel structure measurements by
the methods disclosed herein. Acquisition using multiple
VOIs/locations and multiple acquisition orientations can be done
for correlation with the various lesions appearing on the imaging
sequence.
To study vascular pathology associated with brain disease such as
dementia, the VOI can be positioned in the vasculature near the
cortical region(s) implicated in the dementia. Data can be acquired
in one or more VOIs in one TR. Additionally, in scanners capable of
parallel imaging, multiple VOIs can be defined with simultaneous
record of data to sample extended areas of the brain vasculature.
For example, in dementia in which multiple cortical regions seem to
be damaged, VOIs can be placed in the vasculature feeding these
different regions and data recorded simultaneously.
The usual path for diagnostic development is feature extraction
from the output data towards biomarker identification. Though
feature extraction may define a specific biomarker, often in
diagnostic development extended clinical work (years, dollars) is
needed to strongly correlate biomarkers with pathology. This
reliance on statistical correlation of individual
inspection-derived biomarkers with outcomes is further stymied by
the small size of initial test populations.
Medical data analysis is changing rapidly. Recently developed
analysis techniques enable efficient determination of the total
information content of data acquired using new diagnostic methods.
In contrast to the previous "hunt and peck" method, current pattern
recognition and machine learning techniques enable rapid
correlation with other diagnostic content. In this way, feature
extraction and biomarker development can be done by machine
learning rather than by human observation of data. In effect,
rather than isolating one characteristic (biomarker) from the
entire signal vs. k-value dataset is correlated with other patient
data to yield strong pathology correlations. As such, focusing on
the acquisition end of the embodiments disclosed enables highest
possible SNR as input to the machine learning algorithms used in
this effort.
Computer programs are now adept at determining patterns within
single images as well as performing highly efficient correlation of
data with other medical history/diagnostic information. Data output
from application of the embodiments disclosed, when taken in its
entirety, provides the highest information content. Rather than
reducing the information content through front-end feature
extraction, the entire distribution of signal vs. k-value acquired
from each VOI will be fed into a machine learning algorithm with
pertinent diagnostic data taken by the current standard measures.
For example, correlational data could be liver disease staging
(F0-F5) derived from a doctor's report derived from histology
images, the current gold standard measure for liver disease, liver
function tests (liver serum), and physical exam.
Alternatively, the correlational data could be the output from any
of those tests individually. With sufficient number of cases, this
would enable finer gradations to be defined in disease staging, for
instance, steps in between each stage--F0 and F1, between F0 and
F2, and between F0 and F3, would be possible to define using this
method. Additionally, outcomes--progression to more advanced
pathology, or therapy-induced healing--can provide correlational
data for machine learning algorithms for correlation with textural
assessment from application of the methods disclosed herein.
The assessment stage obtained by the methods disclosed herein can
be mapped on top of a standard MRI morphology image of the diseased
liver. (For easier viewing, an icon can replace the staging
number.) This will facilitate visualization of the disease
variability through the organ. Additionally, these staging values
can be correlated by machine learning with the imaging output
obtained on the same patient by MRE, standard DWI, or perfusion,
for instance to track possible correlations.
A final example of pathology assessment employing the methods
herein is brain tissue. Brain pathology is often problematic to
diagnose and treat because of the sensitivity of the organ to
intervention. Further, changes in cognition and behavior can occur
over a long time span such that the underlying pathology can go
unchecked for years. In AD there is a long pre-symptomatic period,
with underlying, ongoing development of pathology at the molecular
and tissue level, leading eventually to neuronal damage. Though
several have been tested in large clinical trials, there has been a
stunning lack of approval for new therapies for AD or other forms
of dementia. As the population ages, swelling the ranks of those
afflicted with the disease, the situation is dire. The negative
results of several of these clinical drug trials highlight the need
for targeting subjects earlier in pathology development. However,
this requires a diagnostic capable of targeting subjects in the
pre-symptomatic phase. A test to identify such subjects has
remained elusive.
Studies indicate that gray matter is affected earlier than white
matter with dementia onset and progression. The cortical structures
found to be earliest to suffer degradation are the hippocampus and
entorhinal cortex, pathology which leads to memory loss and
disorientation. Recent research applying image processing to 3
T1-weighted MR images of the brain has indicated a statistically
significant correspondence between textural features on images of
the hippocampus and MMSE (Mini Mental State Exam) scores. The
texture is not directly measurable with MR imaging, due to
insufficient resolution, but image analysis metrics correlate
specific textural gradations with glucose uptake reduction in the
hippocampus and subsequent hippocampal shrinkage, a marker for AD,
in addition to the correlations with reduced MMSE scores. These
texture features are not discernible except as a result of image
processing, and their source is not known. Research indicates that
these textural changes precede cognitive decline, and track with
symptom onset. Thus, the hippocampus is a good target for
application of the embodiments disclosed of texture measurement for
pathology assessment.
As the exact etiology of dementia within the hippocampus and
entorhinal cortex is unknown, the embodiments disclosed will be
used to gather a sufficiently complete data set to provide detailed
assessment of tissue texture within the organ--either the
hippocampus or the entorhinal cortex. Both textural wavelength
content and variability, as well as orientation and location
dependence will be measured. Signal acquisition across a range of
k-values, in at least 3 (orthogonal) directions, using a plurality
of contrast methods (as the origin of the texture is unknown), is
requisite to well-characterize the texture. Acquisition of data
across the organ, by defining VOI dimensions to enable fitting the
VOI fit into the organ entirely at different locations will enable
determination of the spatial variability of the texture. By
acquiring signal data across a range in k-space corresponding to
wavelengths of tens of microns out to about 1-2 mm ensures that a
large variety of textural signals contribute to the information
content of the measurement. The embodiments disclosed can be used
in conjunction with any contrast mechanism, such as inversion
recovery, a heightened form of T1 weighting, or diffusion
weighting.
The predictive value of the novel biomarker provided by the
textural data acquired by the embodiments disclosed, towards
assessment of the degree of AD pathology, can be defined by
correlation with a range of diagnostic information from the same
patient. The main correlation marker will be drawn from patient
outcomes--i.e. definitive diagnosis of AD or other dementia--as
this has the highest diagnostic information content, though
definitive diagnosis is well-downstream from the pathology we are
assessing. Additional correlation will be drawn from patient MRI
imaging data on hippocampal shrinkage, a proven, and continuous,
marker of advancing AD (as well as other forms of dementia). This
correlation will be made longitudinally with disease progression,
if possible. Again, changes in tissue texture in the hippocampus
are expected to predate noticeable cognitive decline, and
measurable change in volume via MRI. A third correlative marker is
FDG-PET, as decline in glucose metabolism is expected to occur
early relatively in disease progression. As a fourth correlative
biomarker, the MMSE (Mini Mental State Exam) provides longitudinal
data on cognitive functioning and decline. Genetic predilection for
AD provides an additional marker for correlation with the textural
measure acquired by the embodiments disclosed. While the previous
markers provide downstream correlative value (on the outcome side),
genetic markers exist in advance of any pathology development.
Correlation of this varied set of biomarkers with the data acquired
by the embodiments disclosed in the hippocampus and entorhinal
cortex, across a broad range of patients, will enable a clear
definition of diagnostic content of the use of the embodiments
disclosed for early stage prediction of AD pathology.
Current machine learning algorithms are capable of pathology level
classification of non-specific features, as will be obtained from
MR data acquisition by the embodiments disclosed. As such, the
disclosed sources of correlational data above will be input into
machine learning algorithms to highlight the correlation with
textural features and disease.
Though research has indicated that the hippocampus may be the
earliest affected cortical structure with AD progression, its depth
within the brain results in lower SNR due to distance from the MR
sensing coil. Texture within the neocortex provides a target for
assessment of dementia and other brain pathology that, due to its
proximity to the skull, offers higher SNR. In the healthy brain,
very ordered neuronal architecture is found in the neocortex. The
neurons form in bundles of approximately 50 microns in width and 80
micron spacing, with about 80 to 100 myelinated neurons grouped
together in each bundle. This is the minicolumn organization
visible in histology of neocortical tissue. In specific regions of
the brain that are seen by histology studies to be affected early
in AD progression, this columnar order loses coherence over the
prodromal stages. These changes happen in advance of general brain
atrophy, an often-used marker for AD progression, making them a
better target for early stage diagnosis. Further, the temporal
progression of minicolumn thinning and loss of coherence across
specific brain regions reflects the regionally selective
progression of tangle pathology in Alzheimer's Disease (AD). Hence,
tracking the changes in cortical minicolumns spatially in the brain
using the embodiments disclosed enables typing of dementia, as each
form of dementia follows a specific spatial progression through the
brain.
The structure of these minicolumns in healthy brain can be seen in
FIG. 27, a histology image stained to reveal myelin 2702--the
coating sheathing the neurons. FIGS. 29A-29C are a series of three
histology images stained to reveal the pyramidal neuron cells in
the bundles. FIG. 29A is of neuronal order in healthy brain and
FIGS. 29B and 29C show progressive pathology with AD
advancement--the columnar spacing shrinks and the ordered structure
becomes increasingly random.
Changes in the spacing and order of the minicolumns in these
cortical regions are early harbingers of disease. Though research
in this area is in early stages, as with other pathology, the
underlying tissue changes must predate symptoms. The problem is
that currently there is no technique able to reach the resolution
needed to assess these early-stage changes in the columnar texture.
The embodiments disclosed enables this measurement.
There are several methods by which the embodiments disclosed can be
implemented to measure the change in spacing and order of
neocortical minicolumns. For this measurement to reflect early
stage changes, it would be applied to the regions of the neocortex
that appear to affect behavior earliest in the onset of AD, such as
the temporal cortex. As these regions are in the neocortex on the
outside of the brain, they will yield a strong SNR in a brain coil.
FIG. 28 is a representation showing possible positioning of the VOI
2802a, 2802b, 2802c and 2802d in the neocortex 2804.
As the axonal component of the neurons forming the minicolumn
bundles are sheathed in myelin, a fatty substance, T1 contrast can
be used to highlight the axon bundles against the background tissue
and hence is a good choice for contrast when assessing these
structures.
A difficulty in measuring the columnar spacing results from the
semi-crystallinity of these structures. In healthy neocortex, they
are highly ordered in the vertical (parallel to columns) direction.
As a result, because the acquisition axis of the VOI must intercept
several of these columns to make a measurement, the differential
signal that contrasts the neuronal bundle from the background
tissue is extremely sensitive to orientation of the acquisition
axis. To measure the columnar spacing, the acquisition axis of the
VOI is aligned normal to the length of the columns. Slight
misalignment diminishes contrast--precise orientation is required
for the measurement. To achieve proper alignment, rocking the
acquisition gradient angle over incremental angles of approximately
a degree or two will show a signal resonance at the proper
alignment i.e. consecutively repeating the time varying series of
gradients to produce trajectories through 3D k-space with resulting
k-value sets oriented around the specific k-value to locate
resonance. (The slight curvature of the cortex would be expected to
provide a finite width to this resonance of signal amplitude vs.
angle.) A trajectory through 3D k-space and a resulting k-value set
oriented within 10 degrees of the initially encoded specific
k-value is employed in exemplary embodiments. As the columnar
structure loses coherence with pathology advancement, the width of
this resonance would be expected to broaden, and eventually
disappear when the structure becomes highly random, as shown in the
histology image in FIG. 29C.
Using the embodiments disclosed, acquisition of signal can be at a
(nominally) single k-value, or over a band of k-values defining in
advance of t the measure a finite extent in k-space over which to
acquire the signal.
As the spacing of minicolumns in healthy human brain is
approximately 80 microns, sampling from about 70 microns to 110
microns would encompass the resonance. In exemplary embodiments
this is accomplished by placing the VOI within the cortex and
providing the spatial encode in the range of k-values corresponding
to spatial wavelengths of 40 micrometers to 200 micrometers.
Making measurements in the cortex with the embodiments disclosed
involves these basic steps: 1) A contrast mechanism is selected to
highlight the structure. 2) individual k-values or the span of
k-values for which signal is to be acquired is determined. 3) the
timing of the k-value acquisitions--how many repeats at each
k-value or spread of k-values is determined. 4) the size of the VOI
and orientation(s) of the acquisition axis in the neocortical
tissue are selected.
5) A VOI is positioned in the center of the cortex height, aligning
the acquisition axis parallel to the top and bottom surfaces at the
VOI midpoint, as closely as possible. 6) Signal vs. k-value data is
then acquired with the gradient on or off to measure the minicolumn
spacing; measurement across a broad range of k-values encompassing
on the average spacing of the minicolumns as indicated in the
literature (approximately 80 .mu.m) will ensure coverage of the
width distribution. Signal intensity maximum should occur when the
acquisition gradient is oriented normal to the columns. 6) The
acquisition gradient is then rocked in small angular increments to
look for the signal resonance--the sharpness of the signal
resonance vs. angular deviation reflects the order of the
minicolumns. A sharp resonance indicates ordered structure. A broad
resonance as a function of angular deviation indicates columnar
degradation has introduced randomness into the minicolumn order. 7)
Aligning the gradient to maximum signal return to sweep through the
range of k-values look for textural wavelength resonances--i.e. the
peak of the signal vs. k-value distribution from the texture
distribution. This resonance also can be used to determine
minicolumn order. A sharp peak (high q-value) in the signal vs.
k-value curve indicates ordered structure, the broadness of the
curve is indicative of the degree of loss of order. Locating the
resonance in the signal vs. acquisition angle and in the signal vs.
k-value distribution can be accomplished as an interactive
process.
Data can be acquired at other positions in the cortex or nearby the
original VOI, either within one TR or multiple TRs. Optimal VOI
dimensions for characterization of the cortical minicolumns are
determined by 1) the need to fit the VOI entirely within the
cortex, which is 2-3 mm in height, 2) the requirement to sample
sufficient textural repeats along the encode axis for accurate
assessment of the textural wavelength, and 3) by signal
requirements. Additionally, the smaller the height of the VOI along
the direction of the columns determines the sensitivity to
alignment.
The fewer repeats sampled along the encode axis, the greater the
broadening in k-space of the signal acquired by the embodiments
disclosed. Data can be acquired with the gradient off, relying on
selection of the window width to determine the range of k-values
contributing to the signal. Keeping the spread in k-space small
enough ensures correlation in the signal output.
A change in spacing of neuronal columns indicates pathology
advancement/aging; this can be determined by longitudinal
monitoring of the peak of the signal-magnitude vs. K-value
distribution.
As the structure degrades, the orientation resonance becomes
broader and more diffuse, spread over a larger span of acquisition
angles. Also as the structure degrades, the peak in the signal vs.
k-value distribution becomes broader and more diffuse, spread over
a larger span of k-values (wavelengths). Eventually, no peak will
be visible in either case with progressing degradation of the
minicolumn order, a marker of increasing degree of dementia.
Further, changes in the minicolumns widths with advancing disease
will be reflected in the column spacing, another marker of
pathology.
A variation on this disease marker is the degree of anisotropy of
the columnar order. As the columnar order degrades with progressing
pathology, the degree of anisotropy of the columnar texture also
lessens and the overall cortical tissue texture becomes more
isotropic. The degree of anisotropy can be measured by use of T1,
or other, contrast using the embodiments disclosed, with the VOI
3002 positioned as above, midway between the two cortical surfaces
3004 as seen in FIG. 30 and comparing the signal vs k-value
distribution with the acquisition axis normal to the cortical
surfaces (parallel to the minicolumns), with the signal vs. k-value
distribution obtained with the acquisition axis aligned tangential
to the cortical surfaces 3004 therefore (normal to the minicolumns)
as shown in FIG. 30.
The use of diffusion weighting in brain pathology, including stroke
and brain tumors, is increasing. Diffusion weighted imaging (DWI)
provides an indirect measure of structure at the cellular level, by
applying gradients that first dephase and then rephase signal in a
targeted location.
Stationary water molecules are rephased by the second gradient, but
those that have moved between the two gradients are not, hence
yielding no signal. The difficulty with the technique is that, by
design, it is extremely sensitive to motion. It is also low SNR,
due to the late echo time resulting from the need for the long
diffusion gradients. Use of the embodiments disclosed for data
acquisition when using diffusion contrast can remedy the motion
problem as, though the echo time is still long, data acquisition is
fast enough that the signal loss and blurring due to motion is
minimized. The embodiments disclosed can be used with diffusion
weighting contrast to assess the spacing and order/randomness of
the minicolumns. This measure can be made with the diffusion
gradients applied parallel to the surfaces of the cortex (normal to
the minicolumns), and then normal to the cortical surfaces
(parallel to the minicolumn direction). These two measures enable
assessment of the anisotropy, which will be highest in healthy
brain, pathology then inducing increasing isotropy as the columns
degrade.
Using diffusion weighting, with reference to FIG. 30: applying the
gradient as indicated by Gradient 1 3006 will yield low signal if
minicolumns still intact. Similarly applying gradient as indicated
by Gradient 2 3008 will yield high diffusion signal if minicolumns
still intact.
As minicolumns degrade, signal with the two different gradients
approach each other expect diffusion weighted signal to increase
overall as minicolumns become highly degraded.
A refinement on this measure is through application of the
diffusion gradient in multiple directions for data acquisition and
development of the diffusion tensor similarly to diffusion tensor
imaging (DTI), but with data acquisition being by the embodiments
disclosed. Development of a diffusion tensor requires using at
least 6 non-collinear directions of diffusion gradient orientation
to yield sufficient data to generate the tensor, the eigenvalues of
which determine the level of Fractional Anisotropy (FA) in the
cortex, reflective of the order of the minicolumns. The FA should
change, moving toward more isotropic organization as columnar
organization degrades--an FA value of 1 indicates highest
anisotropy, and a value of 0 indicates maximum isotropy of the
underlying diffusion, hence revealing the order of the columnar
texture.
As with the other types of contrast mechanisms used in conjunction
with the embodiments disclosed, the targeted k-values are selected
by a combination of knowledge of the approximate location in
k-space of the minicolumns from the literature and from measure
when they are still sufficiently ordered to define a clear textural
wavelength signature, and pre-measure to determine the distribution
of signal vs. k-value. One method to achieve this is with a
gradient on to provide sufficient spread in k-space during data
acquisition to enable finer sampling on the subsequent
acquisition(s), though this measure can also be made using gradient
off acquisition.
In the cortex, the mean diffusivity (MD) of water is found to
decrease with increasing dementia. Using the embodiments disclosed
it can be determine if this is due to minicolumn disorder by
measuring the spacing, order, and anisotropy of the minicolumns as
described above. The signal vs. k-value data obtained using the
embodiments disclosed, can be input into a machine learning
algorithm, with correlational data from cognitive evaluation tests
such as the MMSE exam, downstream neuropathology outcomes, and
serum and imaging data.
In addition to Alzheimer's dementia, changes in, or abnormal
morphology in, minicolumn structures occur with Parkinson's
disease, Dementia with Lewy bodies, Amyotrophic Lateral Sclerosis,
autism (autism spectrum disorder is reflected in wider, hence more
tightly packed, minicolumns), and schizophrenia (for which the
normal thinning of the columns with age does not appear to take
place, leading to more widely spaced minicolumns), dyslexia and
ADHD. Hence, the embodiments disclosed can be used to assess degree
of pathology in any of these conditions. Correlation for machine
learning to determine the association between measured data and
pathology can be obtained from cortical atrophy segmentation, MMSE,
doctor's evaluation of degree of pathology from observational data,
etc.
Additionally, the embodiments disclosed can be used with stationary
contrast mechanism to highlight tissue texture changes and flow
contrast to highlight vasculature changes in the vicinity of a
lesion showing up on an MR image, that may indicate stroke or tumor
related pathology.
Studies indicate that gray matter is affected earlier than white
matter with dementia onset and progression. The cortical structures
found to be earliest to suffer degradation are the hippocampus and
entorhinal cortex, pathology which leads to memory loss and
disorientation. Recent research applying image processing to
T1-weighted MR images of the brain has indicated a statistically
significant correspondence between textural features on images of
the hippocampus and MMSE (Mini Mental State Exam) scores. The
texture is not directly measurable with MR imaging, due to
insufficient resolution, but image analysis metrics correlate
specific textural gradations with glucose uptake reduction in the
hippocampus and subsequent hippocampal shrinkage, a marker for AD,
in addition to the correlations with reduced MMSE scores. These
texture features are not discernible except as a result of image
processing, and their source is not known. Research indicates that
these textural changes precede cognitive decline, and track with
symptom onset. Thus, the hippocampus is a good target for
application of the embodiments disclosed of texture measurement for
pathology assessment.
As the exact etiology of dementia within the hippocampus and
entorhinal cortex is unknown, the embodiments disclosed will be
used to gather a sufficiently complete data set to provide detailed
assessment of tissue texture within the organ--either the
hippocampus or the entorhinal cortex. Both textural wavelength
content and variability, as well as orientation and location
dependence will be measured. Signal acquisition across a range of
k-values, in at least 3 (orthogonal) directions, using a plurality
of contrast methods (as the origin of the texture is unknown), is
requisite to well-characterize the texture. Acquisition of data
across the organ, by defining VOI dimensions to enable fitting the
VOI fit into the organ entirely at different locations will enable
determination of the spatial variability of the texture. By
acquiring signal data across a range in k-space corresponding to
wavelengths of ten microns out to about 1-2 mm ensures that a large
variety of textural signals contribute to the information content
of the measurement. The embodiments disclosed can be used in
conjunction with any contrast mechanism, such as inversion
recovery, a heightened form of T1 weighting, or diffusion
weighting.
The predictive value of the novel biomarker provided by the
textural data acquired by the embodiments disclosed, towards
assessment of the degree of AD pathology, can be defined by
correlation with a range of diagnostic information from the same
patient. The main correlation marker will be drawn from patient
outcomes--i.e. definitive diagnosis of AD or other dementia--as
this has the highest diagnostic information content, though
definitive diagnosis is well-downstream from the pathology we are
assessing. Additional correlation will be drawn from patient MRI
imaging data on hippocampal shrinkage, a proven, and continuous,
marker of advancing AD (as well as other forms of dementia). This
correlation will be made longitudinally with disease progression,
if possible. Again, changes in tissue texture in the hippocampus
are expected to predate noticeable cognitive decline, and
measurable change in volume via MRI. A third correlative marker is
FDG-PET, as decline in glucose metabolism is expected to occur
early relatively in disease progression. As a fourth correlative
biomarker, the MMSE (Mini Mental State Exam) provides longitudinal
data on cognitive functioning and decline. Genetic predilection for
AD provides an additional marker for correlation with the textural
measure acquired by the embodiments disclosed. While the previous
markers provide downstream correlative value (on the outcome side),
genetic markers exist in advance of any pathology development.
Correlation of this varied set of biomarkers with the data acquired
by the embodiments disclosed in the hippocampus and entorhinal
cortex, across a broad range of patients, will enable a clear
definition of diagnostic content of the use of the embodiments
disclosed for early stage prediction of AD pathology.
Current machine learning algorithms are capable of pathology level
classification of non-specific features, as will be obtained from
MR data acquisition by the embodiments disclosed. As such, the
disclosed sources of correlational data above will be input into
machine learning algorithms to highlight the correlation with
textural features and disease.
Autism Spectrum Disorders (ASD) as a disease class are diagnosed
solely on the basis of behavior. However, much research has
reported anatomical difference in the brains of people with ASD.
The ability to measure these anatomical variations in vivo would
enable adding pathology-based diagnosis to that based solely on
behavior, and would inform an understanding of the underlying
etiology of this condition.
Along with an enlargement of the frontal cortex, alterations in the
columnar organization of neurons in various regions of the cerebral
cortex are found to be attendant with autism. The neuronal tracts
that span the middle of the cortex form into bundles of
approximately 80 neurons, spaced on the order of 50 microns apart,
forming a columnar organization, the columns running perpendicular
to the cortical surfaces. This organization has been shown in
numerous histology studies to vary in ASD relative to that seen
with normal development. As previously discussed the thinning and
degradation of order in these minicolumns occurs with advancing AD.
In ASD, minicolumn width has been found to be greater than in
normal brains, reducing columnar spacing, and increasing the
neuronal cell density. This change in columnar width varies
spatially throughout the cortex--these variations have been found
in some research to be limited to higher order association areas,
and to spare primary sensory areas, these local differences
mirroring cognitive symptoms. More work is needed to determine the
etiology and correlate pathology with symptoms, as ASD appears to
be highly heterogeneous.
In ASD minicolumns have been found to be on the order of 5% to 10%
wider than in the normal brain. While not a huge difference, across
the hundreds of thousands of minicolumns in the brain, this
variation contributes to a significant difference in brain
organization. Most significantly, this variation in density should
be resolvable by the embodiments disclosed.
Structural change can be measured with the embodiments disclosed
through use of contrast that will highlight the columnar
organization against the background of cortical soft tissue. The
most pertinent contrast here would be a fat-highlighting contrast
such as T1 or IR, to reveal the lipids that sheath the axonal
tracts issuing from the neurons. This contrast may diminish with
advancing pathology as the degradation in minicolumn order could be
attendant with degradation of the myelin axonal sheaths. Casanova
and Trippe, "Radial cytoarchitecture and patterns of cortical
connectivity in autism, Philosophical Transactions Royal Society
B", 2009; Chance and Casanova, Minicolumns, "autism and age: What
it means for people with autism", Autism Science Foundation, August
2015; Donovan and Basson, "The neuroanatomy of autism--a
developmental perspective", Journal of Anatomy, 2017; McKavanagh,
et al., "Wider minicolumns in autism: a neural basis for altered
processing", Brain, July 2015; Opris and Casanova, "Prefrontal
cortical minicolumn--from executive control to disrupted cognitive
processing", Brain, 2014.
Another contrast mechanism that is applicable to tracking the
variation in columnar order is diffusion weighting. This contrast
mechanism has been discussed in some detail above, towards its
application in AD diagnosis. Diffusion weighting measures local
variations in the diffusion coefficient of water, these variations
reflecting tissue changes at the microscopic level. In its use in
imaging, high gradients must be applied for many milliseconds, to
allow enough time to create a sufficient dynamic range in the
measure of diffusion coefficients. This makes for a long echo time
and hence a low SNR due to T2 dephasing. As such, in imaging the
minimal voxel sizes are on the order of 2-2.5 mm on a side to
enable sufficient SNR for the measurement.
Though the underlying phenomena leading to the change in diffusion
coefficients are on the microscopic scale their resolution is
limited in imaging, the size of the voxel required to generate
sufficient SNR resulting in partial volume effects. Further, the
technique is indirect in that the underlying mechanism responsible
for the change in diffusion coefficient, which is averaged over the
voxel, is unknown.
Use of diffusion weighting as contrast, in conjunction with the
embodiments disclosed, would enable direct connection between
changes in very fine tissue textures and the variation in diffusion
coefficient with pathology. By limiting the textural wavelength(s)
(k-values) acquired at each TR, the acquisition would provide
sufficient time to acquire many repeats at the reduced set of
k-values to enhance SNR. If it is desired to probe the power at
multiple wavelengths/k-values, the measure of a reduced set can be
repeated in successive TRs. Again, phase coherence between these
separate measures of k-value is not required. The only requirement
here is that the VOI remain in a tissue region with similar
textural signature. In regions where the tissue texture changes
rapidly spatially, and/or in measurements for which non-negligible
motion is expected, motion correction schemes can be used to
relocate successive VOIs within the tissue region of interest for
each successive measurement.
A further use of diffusion weighting for contrast, to reveal
changes at the level of fine tissue textures, is to use the DTI
(Diffusion Tensor Imaging) scheme. In this method, the diffusion
gradients are applied in at least six non-collinear directions,
enabling determination of the directional diffusion field, to
determine the measure of anisotropy in water diffusion indicative
of a preferential direction/tissue change.
In schizophrenia, reduced neuronal density is seen in the cortex,
in the left hemisphere in females and in the right hemisphere in
males. This reduced density manifests as enlarged minicolumn
spacing, and is attendant with absence of normal aging effects in
the columnar organization in the cortex. It is reasonable to assume
that many neuropathologies dealing with altered cognition,
consciousness, and functioning would exhibit similarly attendant
alterations in the cortical columnar order, the brain region
suffering the attack varying with, and mirroring, the specific
disease presentation. Chance et al., "Auditory cortex asymmetry,
altered minicolumn spacing and absence of ageing effects in
schizophrenia", Brain 2008.
For measure of cortical minicolumnar order and spacing to track
pathology, positioning of the VOI is important so as to generate
highest contrast between the columns and the background tissue. The
VOI is first positioned in the cortical region of interest in the
brain, based on where pathology is expected to strike during
disease progression. Next, based on what is known of healthy
columnar spacing and order, a VOI length, the acquisition axis,
would be selected long enough that it would allow sampling of
several columnar repeats. To ensure high contrast from column to
background, the acquisition axis of the VOI should be positioned as
close to parallel to the cortical surfaces as possible, resulting
in the acquisition axis intersecting the column as close as
possible to normal. This is difficult to do just by use of the
reference image. The optimal method would be to first select the
region of k-space of interest, a band of values peaked near the
healthy minicolumnar spacing. Next, position the VOI parallel to
the cortical surfaces. Then, best alignment can be accomplished by
varying the angle of the tilt of the acquisition axis by a few
degrees on either side of the selected orientation, in steps of
about a degree, looking for the signal maximum within the selected
band in k-space.
The cross section of the VOI can be chosen to be on the order of a
few repeats of the healthy columnar spacing--smaller cross section
favors higher contrast, but also reduces signal. The spread in
k-space can be set either by acquisition with a gradient on to
broaden the acquisition in k-space over the time of the
measurement, or with stepped k-values, by windowing in sample
space. The former procedure is preferred as it allows sampling of a
larger number of textural repeats to better determine where the
power of interest lies. This measure can be repeated across
different ranges in k-space to determine the k-space region on
which to focus for the diagnostic measure.
To optimize the capability of the embodiments disclosed for
diagnosis of autism and assessment of the level of differentiation
of the cortical tissue morphology from normal cortical tissue,
machine learning would be applied. Inputs to such algorithms would
be drawn from a multiplicity of diagnostic measures. Data acquired
using the embodiments disclosed, with selected contrast and
acquisition parameters, would be combined with patient histories,
cognitive testing, exam results, imaging data, and outcomes to be
analyzed via AI/machine learning algorithms
MS is a chronic, inflammatory disease of the central nervous system
characterized by immune-mediated demyelination of nerves. It is a
leading cause of neurologic disability worldwide. Typically, a
disease of young adults, the number of cases peaks in the fourth
decade of life. Compounding the difficulty of understanding the
disease triggers is the fact that disease course varies
considerably from patient to patient. There is
"relapsing-remitting" course with "clinically isolated syndrome"
presentation--an incidence of cognitive symptoms lasting at least
24 hours, "secondary progressive", and "primary progressive"
courses of the disease. A rare variant is the "progressive
relapsing" course which presents with progressive course with acute
relapses. T2 hyperintense lesions, a hallmark of MS, are incidental
findings on an MRI exam in an asymptomatic individual. A. Katdare
and M. Ursekar, "Systematic Imaging Review: Multiple Sclerosis",
Annals of the Indian Academy of Neurology, July 2015. What is
needed in MS is a diagnostic capability that will enable prognosis
of developing pathology towards therapy selection, as well as a
sensitive measure of therapy efficacy. Such measure, though, is
complicated by the various presentations, and a lack of clear
understanding of the various pathology courses underlying
disability.
A growing body of evidence indicates that early intervention is
required in MS to minimize the risk of permanent neurologic damage,
which is often greatest early in the disease course. More sensitive
measures of disease progression are needed to help predict the
course of the disease and assess therapy efficacy. A more sensitive
measure of very early stage disease is clinically necessitated. F.
Piehl, "Multiple Sclerosis--A tuning fork still required", JAMA
Neurology, March 2017.
Magnetic resonance imaging has become a major diagnostic and
research tool in the study of MS. Advanced imaging techniques help
provide a more accurate characterization of tissue injury,
including demyelination, axonal injury, and its functional and
metabolic consequences. The common basis for MS diagnosis is the
dissemination of lesions in "time and space" in the brain, brain
stem, and spinal cord. Gd (Gadolinium) has been used to enhance
lesions in past, but recent findings of long term retention of Gd
in the brain of patients has questioned the safety of its use.
Alternatives to this contrast agent are being sought, as are
alternative methods of highlighting lesions. Additionally, though
tied to a specific temporal variability, white matter lesion load
has only a poor correlation with symptoms of disability. This is
thought to result from the presence of both focal and diffuse
damage appears in the brains of people diagnosed with MS. A method
of assessing the diffuse tissue damage, as well as assessing the
tissue changes within lesions, is required to better understand the
underlying pathology, towards prognosis of cognitive change, and to
sensitively monitor therapy response. However, the imaging
resolution needed to measure the underlying tissue damage within
and surrounding lesions is not directly available with standard MR
imaging, due to patient motion over the course of data acquisition.
Though cerebral MRI has progressed the aim of quantifying
MS-induced tissue changes, from WM lesion assessment to whole brain
microstructural changes, the currently available MRI metrics still
provide no clear explanation for, or diagnosis of pathology, either
on a population-as-a-whole, or on an individual basis. Clearly more
diagnostic information is needed.
A good portion of the MRI market results from the need for
diagnostics for nerve and brain disorders. "MRI Market Primed for
Growth", Aunt Minnie Europe, Feb. 27, 2017. More than that, the
multitude of contrast mechanisms available for MR scanning enable
acquisition of complementary data from within one modality, to
provide a more nuanced read of underlying pathology. What has been
missing in this, however, is direct structural measure at the level
of the tissue texture, the biologic fabric that, in most
pathologies, responds immediately to the chemical changes that
drive disease. In some diseases, the chemical changes that drive
pathology are known and measurable but, in others, the earliest
measurable change is in the structural fabric of the tissue.
However, this change is not measurable by imaging due to the
resolution limits set by patient motion. Therefore, though MRI
offers exquisite tissue contrast, it cannot resolve the sub-mm
diffuse tissue changes that are the early harbingers of
disease.
In past, MS was characterized as a disease of WM (White Matter)
tracts and the CNS (Central Nervous System) with the focus on
demyelination of the axonal tracts that carry signals from cortical
grey matter to other parts of the brain. However, many recent
imaging and pathology studies point to clear involvement of the
grey matter. Cortical demyelination, which is seen to be present in
early stage MS, may be a pathologic correlate of irreversible
disability. Gray matter demyelination is extensive in most MS
patients, and clear association between the lesion load in grey
matter and cognitive impairment has been made. However, detection
of GM lesions is difficult with standard MR contrast techniques,
hence correlation with clinical symptoms remains problematic.
Wegner and Stadelmann, "Grey Matter Pathology and Multiple
Sclerosis", Current Neurological and Neuroscience Reports, 2009;
Popescu and Lucchinetti, "Meningeal and Cortical Grey Matter
Pathology in Multiple Sclerosis", BMC Neurology 2012; A. Katdare
and M. Ursekar, "Systematic Imaging Review: Multiple Sclerosis",
Annals of the Indian Academy of Neurology, July 2015. Further,
though conventional MR sequences, specifically T1, T2, and T1 with
Gd contrast, are sensitive for detecting WM lesions throughout the
CNS, patient motion limits their ability to assess the underlying
tissue damage within and outside the lesions. The diagnostic
information that is missing here is the underlying changes in the
tissue texture within the brain--both in regions of WM tracts and
in the cortical regions (GM) occurring as a result of disease. Due
to its immunity to patient motion, the embodiments disclosed can
provide this measure.
MR techniques that generate contrast originating at a molecular and
cellular level have been applied to the problem of developing a
more complete understanding of the tissue changes underlying both
lesions and the diffuse tissue damage inherent with MS. These
non-conventional techniques, such as Magnetization Transfer Imaging
(MTI), Diffusion-Weighted Imaging (DWI), and Diffusion Tensor
Imaging (DTI) provide an indirect measure of the effects of
disease-induced degradation of WM and GM. The difficulty with these
measures is that, as they are indirect, changes in the signal
intensities that they measure can arise from various
pathology-related tissue changes--assigning a specific underlying
cause is problematic. DTI does a good job of neuronal fiber
tracking through the brain, showing the macroscopic holes that
appear in the tracts due to pathology advancement. But it cannot
determine the exact source of these changes on the level of fine
tissue texture--i.e. the earlier and more sensitive measure of
disease progression. Lesions are non-specific and may indicate
areas of inflammation, demyelination, ischemia, edema, cell loss,
gliosis. A better understanding of the fine-scale pathologic
changes resulting in the observed cognitive impact of MS is
needed.
Though lesion size, number, and spatial and temporal distribution
are clear contributors to disease progress evaluation, T2 weighted
MRI lacks pathologic specificity and specific predictive
capability.
WM pathology in MS is dominated by an inflammatory response leading
to degradation of the myelin sheath surrounding the axons
comprising the neuronal tracts that run through the brain. Direct
measure of myelin loss at an early stage, before the appearance of
well-defined lesions in the WM, would be a most useful diagnostic
measure towards early treatment. Single axons are on the order of 1
.mu.m, hence combined degeneration is required to produce a
measurable signal. The marker sought is the decrease in myelin
along the tracts as axonal degeneration progresses. The localized
degradation appears as a WM lesion in T1 and T2 weighted
images.
Due to the complexity of MS pathology, a single diagnostic measure
would not be expected to completely unravel the underlying causes
of pathology onset and progression. The ability of computers to
store and process ever larger data sets has enabled complex image
processing and interpretation, using multiple measures of image
data obtained under conditions of different contrast, from a single
patient. Further, computation capability has made it possible to
more accurately derive biomarkers from new MR diagnostic measures,
through use of machine learning algorithms that correlate data
obtained by differing MR contrast, differing modalities, combined
with patient metadata and outcomes, across an entire
population.
Along with the needed development of more sensitive/specific MRI
diagnostic approaches that can provide earlier diagnosis, improved
post-processing is needed to maximize information extraction.
Bakshi et al., "MRI in multiple sclerosis: current status and
future prospects", Lancet Neurology, July 2008.
Combination of diagnostic information has the best chance of
revealing underlying pathology in MS, especially given the ability
to combine these measurements using AI/machine learning/deep
learning algorithms. However, though the correlation of data is
more powerful than single measures, high information content inputs
to the algorithm drive its sensitivity and efficacy. In its ability
to directly measure the very fine textural changes in affected
brain tissue, the embodiments disclosed provides a key piece of
data towards enabling sensitive measure of MS progression. Further,
it provides a high-information-content measure of textural
morphology, which can be applied: 1) as a correlational measure
towards calibration of other indirect MRI pulse sequences/contrast
methods, such as DWI and MTI, or 2) it can be run in an integrated
mode with any specific contrast mechanism selected to provide
highest tissue contrast, the MR data being acquired using the
embodiments disclosed with the tissue contrast being provided by
whatever contrast mechanism provides optimal contrast. This may be
standard contrast such as such as T1 and T2-weighting, or more
advanced measures such as DWI or MTI. (FIGS. 24 and 25 as discussed
above, demonstrate an integrated DWI/texture pulse sequence).
Inflammation in MS causes both demyelination of neuronal tracts and
axonal injury. Brain atrophy follows and is reflected in cortical
thinning, which can be measured in MRI using post acquisition
segmentation. However, by the time cortical atrophy is measurable,
significant neuronal damage has already occurred in the cortex,
atrophy being the macroscopic mirror of integrated tissue damage.
Direct measure of tissue change/myelin loss at an early stage,
before the appearance of measurable atrophy or well-defined
lesions, is needed as a diagnostic measure enabling early
treatment. Fox et al., "Advanced MRI in Multiple Sclerosis: Current
status and future challenges", Neurologic Clinics, May 2011.
Single axons are on the order of 1 .mu.m, hence combined
degeneration is required to produce a measurable signal. However,
in the cortex, neurons bundle together in groups of about 80,
enabling a sufficiently sensitive measure of tissue change to track
the degeneration underlying cortical thinning. This is largely
equivalent to the cortical damage inherent in progressing
Alzheimer's disease. Degeneration in these columns, as indicated by
lack of order, and degrading myelin, is one of the early markers of
MS.
Another contrast method that has been applied in an attempt to
quantify myelin degradation is Magnetization Transfer Imaging
(MTI). Water bound in macromolecules such as myelin decay too
quickly to allow recording of their MR signal, hence measure of
signal strength directly is not possible. However, due to dipole
interactions between free water in the brain and bound hydrogen
protons, changes in the ratio of the free and bound pool of protons
can be measured. Though this is a sensitive measure of change of
water content, as with difffusion imaging, the underlying mechanism
causing the change can be ascribed to multiple pathologic
phenomena. MTR associated with myelin content but, as it is also
affected by water content, from say edema and inflammation, you
can't tell exactly what is causing the change in MTR. MTR changes
by both changes in the free hydrogen pool (water content) and the
bound hydrogen pool (e.g. those bound to proteins and lipids in
cellular membranes such as in myelin). Comparison with
histopathology has shown reasonably good correlations with both
demyelination and remyelination, and with overall neuronal density.
Therefore, association of changes in MTR as reflecting myelin
content is not at all straightforward. This is the power of direct
structural measures--the interpretation relies only on the contrast
mechanism Vavasour et al., "Is the Magnetization Transfer Ratio a
marker for myelin in Multiple Sclerosis", Journal of Magnetic
Resonance Imaging, 2011.
As with the incorporation of the embodiments disclosed and
diffusion weighting within one pulse sequence, the embodiments
disclosed can be combined directly with MTI contrast, to highlight
structures whose contrast arises from variations in water
content.
DWI and DTI yield different insights, though both measure the
microscopic Brownian motion, or diffusion, of water molecules,
which is hindered by cellular structures and changes with
pathology. In healthy axonal tracts water diffuses preferentially
along the tract, but as inflammation induces axonal degeneration,
water diffusion becomes more isotropic. The degeneration of these
tracts is reflected in the change in the preferred direction for
water diffusion at the cellular level, or Fractional Anisotropy
(FA) as measured by DTI. DWI measures the Mean Diffusivity (MD),
regardless of direction. In general, low-fractional anisotropy (FA)
and high-mean diffusivity (MD) are found in MS lesions, but values
are highly heterogeneous. However, these measures are
inferred--i.e. it is necessary to posit a cellular level mechanism
for the observed decrease in diffusion magnitude and
directionality. For example. changes in diffusion can be due to
inflammation or edema, or byproducts of myelin degradation.
Another method to assess demyelination is by multi-echo recording,
which allows measure of T2 relaxation, a figure which reflects
water/fat content. This is known as T2 relaxometry, and when used
in integrated form with the embodiments disclosed enables measure
of tissue structure differentiated by water content.
An exemplary MS assessment would include visualization of lesions
in T2 and T1 weighting--dissemination in space and time. This would
be a longitudinal record. Combining different MR-based measures,
sensitive to different aspects of MS pathology to increase
understanding of the mechanism underlying accumulation of
irreversible disability. Employ perfusion MRI to quantify cerebral
blood flow and volume; multi-channel receiver coils to examine the
interior of lesions. Brain atrophy measures are employed for
measuring cerebral volume changes and look at correlation with WM
tract damage.
Machine learning algorithms may then be applied to evaluate
combined data from current diagnostics and data obtained by
applying the embodiments disclosed with various contrasts and
acquisition parameters--structured or unstructured.
To accommodate pathology analysis for the examples provided, a
salient feature of the embodiments disclosed is that they can be
run in an integrated pulse sequence mode with other MRI sequences.
The basic structure of the embodiments disclosed--data acquisition
across a sparsely-sampled k-space trajectory, at one tissue
location at a time--is operable in conjunction with most
contrast-generating mechanisms.
Use of the embodiments disclosed with diffusion-weighting contrast
was disclosed in FIGS. 24 and 25 which depict an integrated pulse
sequence using the embodiments disclosed in conjunction with
diffusion weighting, with two different positionings of the
diffusion gradients within the sequence.
Such an integrated sequence could be repeated with the diffusion
gradient applied along multiple axes, similarly to DTI (Diffusion
Tensor Imaging). The output dataset would then allow development of
a diffusion tensor, enabling determination of the FA (Fractional
Anisotropy), a reflection of water flow pathways in the tissue
which reflect cellular-level changes.
Along with application of both DWI and DTI contrast towards typing
MS lesions and determining underlying pathological tissue changes,
a sequence that enables assessment of changes in fraction of bound
and free water, MTI (Magnetization Transfer Imaging), can be used
to help assess myelin destruction and regeneration in progressive
pathology. The aim of the MTI technique is to track changes in
bound water vs. free water in tissue. The T2 decay time of bound
hydrogen protons is too fast to enable direct signal recording.
Instead, selective RF excitation of the bound pool of protons is
done, resulting in subsequent excitation transfer to the free pool
via dipole-dipole interactions. This results in saturation of the
free pool and, hence, signal is reduced following subsequent
application of a standard RF MRI pulse.
As with diffusion weighting, this is an indirect technique and
hence different interpretations may fit the measured data--water
changes can be due to edema or inflammation as well as
demyelination.
One possible technique for pathology assessment is to apply the MTI
technique and then compare the image recorded to textural measure
acquired in the same tissue region using the embodiments disclosed
and a standard tissue contrast, such as T1 or T2 weighting. In this
case, the embodiments disclosed could provide an assessment of
tissue degradation, which could be used as a pathology-specific
calibration of the MTI technique. However, a more powerful
alternative would be an integrated pulse sequence, in which the
embodiments disclosed would be used in conjunction with
magnetization transfer contrast--i.e. would acquire high-resolution
measure of texture with texture contrast between structures of
differing bound and free water concentrations provided by the MT
contrast. This integrated sequence technique could be applied in
pathologies for which there is a clear differentiation between the
type of water (free, or bound to macromolecules) associated with
the measured textural elements. Pathology in many neurologic
diseases, such as MS and AD, involves changes in the myelin coating
neuronal structures. Myelin contains bound hydrogen protons; free
water moves in as the myelin degrades. Hence this integrated
sequence could provide a much-needed measure of such pathology.
And, unlike direct application of the MT imaging sequence, the
integrated pulse sequence measure applied to tissue informs a
clearer understanding of the pathology-linked changes in tissue
texture.
Another target for integrated pulse sequence acquisition would be
relaxometry. Information about pathology-linked changes in tissue
can be obtained through measure of the decay time of the RF
excitation--either T1, T2, or T2*--which provides information about
the specific tissue environment. Hydrogen protons in different
chemical environments exhibit different relaxation times. The most
commonly used figure, T2 decay time, is dependent on spin-spin
interactions. Variations in T2 relaxation can thus be used to
discriminate among chemical environments in tissue, and can
heighten tissue contrast. For instance, as myelin decomposes in
diseases such as AD and MS, free water moves in. This change is
reflected as a change in the local T2 time constant. The T2 decay
constant is obtained by acquiring data at various times following
the spin echo (or even in advance of it) as the signal decays. In
relaxometry, measurements obtained in different voxels are often
mapped to form an image revealing spatial variations, often
pathology-induced, in T2 decay time. This mapping is subject to the
resolution limits set by patient motion and SNR considerations, and
is not capable of resolving fine tissue textures. However, by using
a pulse sequence to acquire data by the embodiments disclosed,
repeating measures at specific k-values to track signal decay, an
integrated measure of very fine tissue texture can be achieved,
with T2 relaxation rate providing the tissue contrast. The basic
sequence would then entail defining and exciting tissue in the VOI,
applying a gradient pulse to wind up to a specific k-value (point
in k-space), and measuring the signal at successive times as the
signal decays. By this method, information is obtained on the
chemical environment of the tissue textures contributing to that
point in k-space--i.e. the tissue environment of textural
structures that repeat with the frequency associated with that
k-value. For instance, as water has a specific T2, measure of T2
decay rate can be used to gauge changes in the free water content
of the specific textural structures that contribute to signal power
at that k-value.
Alternatively, a range of points in k-space can be sampled in a
single TR, the various k-values being measured in succession, and
then the measure being repeated multiple times while the signal
decays, to track the signal decay at each k-value and enable
determination of k-value vs. T2.
T2 relaxometry in human brain has been successfully used to
differentiate normal from abnormal tissues. Research studies have
also demonstrated the potential of relaxometry for early breast
cancer detection and monitoring of therapy response. The technique
has also been used to identify abnormal breast tissue,
distinguishing adipose from glandular tissue types by their
distinctly different T2 values. Carneiro et al., "MRI Relaxometry:
Methods and Applications", Brazilian Journal of Physics, March
2006.
This measure could be done similarly looking at T2* decay, by using
a gradient echo sequence to form the echo.
T1 relaxometry can be done in integrated sequence combination with
the embodiments disclosed, though multiple TRs are required to
track the T1 decay constant. This means that motion between
acquisitions can lead to dephasing of the measure. However, as long
as the VOI remains in a similar tissue environment, the measure
needed is simple k-value vs. T1. Further, if the tissue region
under study changes rapidly spatially, real time motion correction
can be used to ensure that the VOI is repositioned at each TR to
stay in the same region of tissue. Again, the requirement here is
only to remain in the same tissue region, not to maintain textural
phase coherence.
In certain diseases, the embodiments disclosed can provide
complementary data to improve pathology assessment when used in
conjunction with MRS (Magnetic Resonance Spectroscopy). MRS is a
noninvasive technique that enables detection of metabolites,
naturally occurring biochemicals that are used in specific
metabolic activities. Commonly measured metabolites are creatine,
inositol, glucose, N-acetylaspartate, and alanine and lactate, the
latter two being elevated in some tumors. MRS has been used to
study relative changes in metabolites in brain tumors, as a result
of strokes, seizures, AD progression, and depression, as well as
being applied to study muscle changes as a result of pathology.
Although an abundance of studies show metabolic changes in the
brain (and muscles) in subjects with various diseases, at present
MRS is little used in the clinical evaluation of subjects. This is
partly due to a lack of standardized methodology between clinical
sites and overlap of spectral patterns between different
pathologies (i.e., relative lack of specificity). Water suppression
techniques are required, usually accomplished through saturating
the water protons, as the ratio of water to metabolites is on the
order of 10,000:1. Combining data obtained by the embodiments
disclosed with MRS data could help in the calibration of the
spectroscopic data and lead to a more powerful diagnostic by
combination. This endeavor may bring high sensitivity and
specificity metabolic information without biopsy. While MRI can
locate a tumor, information from the embodiments disclosed combined
with MRS can reveal tumor aggressiveness and type, allowing therapy
targeting and monitoring.
As one example, clinical studies have found increased myo-inositol
and decreased N-acetylaspartate in the brain of patients with
suspected Alzheimer's disease, this trend continuing with disease
progression through MCI (Mild Cognitive Impairment) into full-blown
AD. As such, correlation of MRS data obtained in the cortical
structures affected in early disease with the change in tissue
texture in the cortex as measured using the embodiments disclosed,
would strengthen the role of metabolite levels as a marker for
pathology advancement, while developing a correlation between
specific tissue damage and AD stage. Gao and Barker, "Various MRS
application tools for Alzheimer's Disease and Mild Cognitive
Impairment", American Journal of Neuroradiology, June 2014.
Research to date has shown that local metabolite levels can
indicate changes from normal tissue, often correlating with
pathology development. For instance, measure of metabolite
signature spatially across a tumor can be analyzed to measure
tissue heterogeneity, an indicator of tumor aggressiveness. The
embodiments disclosed can provide measure of the spatial variation
of angiogenic vasculature across that same tumor to correlate the
degree of vascular density and disorder with the MRS metabolite
read.
The disclosed embodiments can be employed to look for heterogeneity
across a region and at changes in k-space power spectrum with
reference to normal spectrum.
Another target for combining the embodiments disclosed with MRS is
for clinical evaluation of tumor development. Tumor assessment is
required for typing and for determining target volume for radiation
therapy. Brain tumors exhibit markedly different MRS spectra from
normal brain tissue. Further, tumor regions exhibit clear
metabolite inhomogeneity, the spectrum from the necrotic core of a
high-grade brain tumor being quite different from that from the
actively growing rim. Peritumoral edema exhibits a much different
metabolite complement than is found in a region of tumor invasion
into surrounding brain tissue. MRSI (MRS Imaging) can be used to
map out the metabolite variability in the region of a tissue.
However, the limited spatial resolution (about 1 cm3) makes imaging
of small tumor regions problematic due to the relatively large
voxel size and to partial volume effects. While the clear variation
in metabolites in tumor regions point to the potential for
application of MRS, it has not been accepted as a routine clinical
tool.
While MRI is without doubt the most sensitive modality available
for the detection of brain tumors, its specificity is
low--different tumor/lesion types, can share a similar MRI
appearance. Determination of tumor grade, or differentiating
between neoplastic and non-neoplastic lesions, is important, as
high-grade brain tumors need to be treated more aggressively than
low-grade tumors. If a lesion can be confidently diagnosed as
non-neoplastic, an invasive brain biopsy procedure may be avoided
and a different treatment course, depending on the lesion etiology,
may be considered. Differentiation between tumors and
non-neoplastic lesions using conventional MRI may be challenging.
While MRI is a sensitive technique for detection of brain lesions,
the specificity and capability of conventional MRI for
distinguishing between benign and malignant lesions is limited.
Horska and Barker, "Imaging of Brain Tumors: MR Spectroscopy and
Metabolic Imaging", Neuroimaging Clinics of North America, August
2010.
Data obtained with the embodiments disclosed can be combined with
that obtained by MRI and MRS, to provide better specificity for
pathology assessment. The embodiments disclosed, in their ability
to measure fine structure, can provide pertinent information to
assist in tumor typing, by assessing the vasculature within and
surrounding the tumor to determine the degree of angiogenesis
across the tumor from the center out past the periphery of the
lesion as seen with MRI, part of the measure being evaluation of
extent of the angiogenic vasculature into the surrounding tissue.
In this way, differentiation between aggressive/non-aggressive
tumors can be made with much better certainty than can be achieved
using only MRS and MRI. The metabolite variation that arises from,
say, edema, will be associated with a very different tissue
texture, than would that associated with angiogenic vasculature.
Embodiments disclosed measures angiogenic changes across tumor.
A typical workflow for application of an integrated pulse sequence,
combining the embodiments disclosed with additional novel contrast
methods, might be accomplished as shown in FIG. 31.
Select a desired contrast needed by identifying tissue types of
interest, step 3102.
Reference images are then generated for localization in anatomy
using standard contrast such as T1, T2, T2*, IR, step 3104.
Apply the integrated pulse sequence with selected contrast, such as
DWI, DTI, ASL, MTI, step 3106, and apply the embodiments disclosed
for texture characterization in a single acquisition sequence
combining the localized, sparsely sampled in k-space, fast
acquisition of the embodiments disclosed with the selected contrast
generating mechanism, step 3108.
The novel features of the embodiments disclosed that enable much
higher resolution measurement than is achievable with MR imaging
are 1) sampling at targeted spatial locations, the size of the
sampled volume being determined by the targeted disease/pathology,
and 2) selective sampling in k-space. In MR imaging, acquisition is
across a large, spatially-encoded 3D volume, and encompasses
continuous k-space measure from k=0 up through to the highest
k-value of interest. Such a measure requires acquisition of a very
large data set over a temporal course long enough that patient
motion limits feature resolution. By localizing the measure to one
location in sample space, and sampling only highly selective
regions in k-space, the embodiments disclosed provides immunity to
patient motion, thus enabling a high resolution textural measure to
be acquired within one TR. The measured textural data is similar to
that acquired by biopsy, with none of the procedural risks.
Further, the sampling errors inherent in biopsy/pathology are
obviated because, using the embodiments disclosed, an entire organ
can be covered with individual, motion-immune, localized
measurements.
The k-space sampling required to adequately characterize tissue
texture varies both with disease, and with the stage of pathology
development. Though, as with many measurements, a basic knowledge
of the disease can be used to select acquisition parameters,
enhanced parameter optimization can be achieved through use of
"scout" acquisitions, that provide general information on the
distribution of power through k-space at a certain location. For
instance, as the optimal length of the sampled volume, the VOI
(Volume of Interest), varies with the textural wavelength(s) of
interest in the tissue under study, an idea of the approximate
range/values of interest in k-space would help in selecting VOI
dimensions.
In bone, say, as the trabecular number decreases with degradation,
it would be advantageous to vary the VOI length to keep the ratio
of feature size (textural number) to sampling length relatively
constant. In this case, TbN is the feature length of interest, not
TbSp or TbTh, as TbN determines the repeat number relative to the
VOI acquisition length. Use of scout images to determine the
relative position(s) in k-space of the peak signal power, would
enable optimal setting of the VOI length.
To affect the Scout measure, one method would be to select optimal
tissue contrast based on what is known of the pathology, and
acquire data for sufficient time and TRs to gauge generally where
the power lies in k-space for a single orientation acquisition.
These scout measures can be made using gradient ON acquisition to
sweep through a range of values, keeping the sweep slow enough to
obtain sufficient SNR to gauge where the textural power lies in
k-space. Thus, scout measure would be accomplished by first
acquiring signal data across a large enough region in k-space to
encompass the textural k-values associated with the tissue under
study across the range of health into disease. Real-time decision
on what range(s) demonstrate importance in the initial scan can
then be selected for more detailed tracking by slower gradient ON
acquisition, or targeting specific k-values to measure. Data
acquisition will then be successively focused on narrower and
narrower ranges to zero in on k-space regions that hold the highest
information content. In this undertaking, it must be kept in mind
that, regions of little textural features can, in their very lack
of texture, be of import in disease progression
In some cases, where pathology is mirrored in changes across large
regions of k-space, acquisition could be with gradient on and slow
sampling across the entire region.
As another example, scout acquisitions could be used to determine
the k-value of interest for a relaxometry measure. Since most
biologic tissue textures are non-crystalline, a finite band in
k-space, representative of the textural k-value span, could be
identified using gradient ON acquisition. This could be achieved by
successively sampling sub regions across k-space to find the region
of interest where the textural power lies. Once the k-band of
interest is determined, the decay of RF excitation across that band
can be measured as the signal decays, the sampled region being
selected using gradient ON acquisition.
Scout images can be used to investigate sensitivity to exact
positioning.
Thus, as shown in FIG. 32 a procedural flow using scout
acquisitions might entail:
Setting a VOI based on knowledge of the type of underlying tissue
and disease, step 3202, and acquiring signal data across some broad
regions in k-space. The regions can be set either by acquisition
with a gradient on to broaden the acquisition in k-space over the
time of the measurement, step 3204, or with stepped k-values, by
windowing in sample space, step 3206. The former procedure is
preferred as it allows sampling of a larger number of textural
repeats to better determine where the power of interest lies. This
measure can be repeated across different ranges in k-space, step
3208, to determine the k-space region on which to focus for the
diagnostic measure.
The scout acquisition can be repeated as needed across various
selected ranges in k-space, within one or multiple TRs, step 3210.
The loss of coherence between TRs does not matter as long as the
measure remains within a similar region of tissue texture. Real
time repositioning could be used here as needed for gross
repositioning, step 3212.
This scout method can be repeated in as many different
orientations, step 3214, and as many different locations as
desired, step 3216.
Using the information obtained for the power(s) of interest, VOI
dimensions can be selected to allow sampling of a minimum of 4
textural repeats (more would be better, though the shorter the VOI
the easier it is to maintain textural homogeneity across its
dimensions), step 3218, and data will be acquired across the
salient ranges in k-space, in one or multiple TRs.
It is to be noted that features of interest are not just in the
ranges where there is much spectral power, but also includes ranges
that are of interest due to a specific lack of signal intensity
there.
As briefly described above with respect to various applications of
the embodiments disclosed, machine learning in development and
application of medical diagnostics can be applied to facilitate 1)
calibration of the diagnostic and determination of optimal data
acquisition parameters, 2) identification of the biomarkers of a
disease, and 3) ongoing use of the diagnostic method in both
individual and population health spheres to ensure optimal
extraction of diagnostic information. Machine learning can be
applied in either a supervised learning method, when it is known
what output quantity/biomarker (such as trabecular bone thickness)
is to be measured, or it can be run in an unsupervised mode, in
which the algorithm searches the data sets it is given looking for
common features. In the former case, supervised learning, the
accuracy with which a new diagnostic measures the known quantity is
determined by comparison to some sort of ground truth measure, and
the machine learning can be used to optimize the data acquisition
parameters for the diagnostic. In the case of unsupervised
learning, once the features common among the various data sets are
extracted--in the case of the embodiments disclosed, the power
distribution in certain regions of the textural wavelength
spectrum--they can then, if desired, be correlated with other known
information about the targeted tissue such as state of
health/disease.
Machine learning can be an instrumental part of calibrating the
embodiments disclosed as a diagnostic tool in each disease in the
large range of diseases for which variation in tissue texture is a
marker of disease onset and progression. The application of machine
learning towards this goal is facilitated by use of a source of
ground truth measure of pertinent tissue texture, to provide input
for determination of the salient textural features that track
pathology, features which are currently not measurable in vivo, and
for validation of the diagnostic data obtained by the embodiments
disclosed. This ground truth can be provided through use of tissue
samples from various organs, reflecting various states of health
and pathology in disease. Because there is no motion blurring, use
of ex vivo tissue enables generation of high quality ground truth
data sets for calibration of the embodiments disclosed by use of
techniques such as microCT, pathology staining, and MRI microscopy.
(Szeverenyi et al., MR imaging of liver microstructure in hepatic
fibrosis and cirrhosis at 11.7T, ISMRM 2016).
The work flow for calibration of the embodiments disclosed for
application in diagnosis of targeted diseases is described in FIG.
33 as the following: Obtain high resolution 2D or 3D data sets from
selected tissue samples by use of microCT, MRI microscopy, or
pathology, step 3302. Use computer simulation to simulate data
acquisition by the embodiments disclosed for texture
characterization from these data sets by using the data sets as
input for simulating application of a selected contrast mechanism,
selectively exciting a simulated volume of interest (VOI) employing
a plurality of simulated time varying radio frequency signals and
applied gradients, applying a simulated encoding gradient pulse to
induce phase wrap to create a spatial encode for a specific k-value
and orientation, the specific k-value determined based on the
texture within the VOI, initiating a series of simulated gradients
to produce k-value encodes, a resulting k-value set being a subset
of that required to produce an image of the VOI, recording multiple
sequential samples of simulated NMR RF signal encoded with the
k-value set and post processing the recorded NMR signal samples to
produce a data set of signal vs k-values for k-values in the
k-value set, to characterize a simulation of the textural features
of tissue in the VOI, step 3304. Compare the features in the 2D/3D
data sets with the measures of these features obtained by simulated
application of texture characterization, step 3306. Simulate
acquisition of data by the embodiments disclosed for texture
characterization across a high number of VOIs positioned within the
tissue datasets, step 3308, and apply supervised machine learning
to this data to optimize acquisition parameters such as VOI
dimensions and acquisition direction, using best resolution of the
targeted feature measure as an endpoint, step 3310. Use
unsupervised machine learning across the various defined VOIs in
tissue with specific disease markers to identify salient features
additional to that called out for supervised learning, step 3312.
Use machine learning algorithms to correlate those features with
whatever information is known regarding disease onset and
progression in the tissue samples towards biomarker identification,
step 3314. Determine the sparsely sampled data set is that is
needed for measuring the tissue biomarkers towards disease
diagnosis, step 3316. Use machine learning to determine the
strength of the diagnostic assessment provided by the embodiments
disclosed, step 3318. Acquire data by the embodiments disclosed in
the actual SNR environment of the MR scanner, on the same tissue
samples, for comparison to the ground truth datasets, step 3320.
Repeat the above steps towards optimization of acquisition
parameters and calibration of the embodiments disclosed towards
high resolution, robust textural measure, step 3322.
As previously described, machine learning may be employed using the
tissue texture measurement methods of the various embodiments to
enhance determining pathology of a tissue type. A contrast
mechanism is selected enhancing the contrast between component
tissue types in a multiphase biologic sample which may also be
employed for measurement with a MR imaging process. The selected
contrast mechanism is applied and a volume of interest (VOI) is
selectively excited employing a plurality of time varying radio
frequency signals and applied gradients. An encoding gradient pulse
is applied to induce phase wrap to create a spatial encode for a
specific k-value and orientation, the specific k-value determined
based on texture within the VOI. A series of gradients is then
initiated to produce k-value encodes, a resulting k-value set being
a subset of that required to produce an image of the VOL Multiple
sequential samples of the NMR RF signal encoded with the k-value
set are recorded and post processed to produce a data set of signal
vs k-values for k-values in the k-value set, to characterize
textural features of tissue in the VOL Machine learning is then
applied to a power density distribution of a textural wavelength of
the k-value set to identify bio-markers for diagnosis of pathology
of the tissue.
The method may be further enhanced by applying machine learning to
identify a correlation between textural features and features in a
power density spectrum of the textural wavelengths. Machine
learning may also be applied to the textural features using
additional sources of diagnostic information such as patient
histories, exam records, imaging, serum markers, physical
performance, and cognitive tests for extraction of diagnostic data
to determine a disease assessment. Machine learning may also be
applied to determine weighting of the various diagnostic
information sources in the ultimate diagnosis.
Input for machine learning may also be created by selecting a
plurality of biologic phantoms having tissue pathology from healthy
through diseased. A contrast mechanism enhancing the contrast
between component tissue types in each biologic phantom is selected
for measurement with a MR imaging process and the selected contrast
mechanism is applied in an MR pulse sequence. A volume of interest
(VOI) in each biologic phantom is excited employing a plurality of
time varying radio frequency signals and applied gradients. An
encoding gradient pulse is applied to induce phase wrap to create a
spatial encode for a specific k-value and orientation, the specific
k-value determined based on anticipated texture within the VOL A
series of gradients to produce k-value encodes, a resulting k-value
set being a subset of that required to produce an image of the VOI
are then applied and multiple sequential samples of the NMR RF
signal encoded with the k-value set are recorded to provide texture
measurement of each of the biologic phantoms.
Following calibration and optimization of the embodiments disclosed
in various disease applications, the texture measurements produced
by the embodiments would then be used as clinical diagnostic tools.
Due to the ability to measure textural features to high-resolution
in a size realm previously unmeasurable, and the fact that tissue
changes are a very sensitive measure of pathology progression, the
embodiments disclosed produce high information content data. Also,
as it is a fast and hence minimal cost to add the disclosed
embodiments to an MRI scan, barriers to adoption and use are low.
As such, the disclosed embodiments will be one of the important
drivers in the clinical diagnosis of disease, and can thus help in
weighting the efficacy of the various other sources of diagnostic
information that are applied. Machine learning algorithms would be
applied to correlate all the data from the multiple sources of
pertinent data acquired towards patient health assessment,
including data acquired by the embodiments disclosed, patient
histories, exam records, imaging, serum markers, physical
performance, cognitive tests, and any other types of diagnostic
information available. The range of diagnostic information
available on a patient would be fed into a machine algorithm that
would, using the sum of this data, provide both an optimized
diagnosis and a weighting of the importance of the various
diagnostic inputs to the algorithm, as well as an evaluation of the
level of certainty of the diagnosis. This ability to assess
diagnostic accuracy and weighting in clinical practice would be
informed by use of machine learning in the sphere of large
population health data sets towards determination of the efficacy
of many currently used diagnostics. Additionally, correlation with
all other data sets will provide ongoing calibration and
optimization of the embodiments disclosed, as well as maximum
extraction of diagnostic data.
Having now described various embodiments of the invention in detail
as required by the patent statutes, those skilled in the art will
recognize modifications and substitutions to the specific
embodiments disclosed herein. Such modifications are within the
scope and intent of the present invention as defined in the
following claims.
* * * * *
References